Open access peer-reviewed chapter

Immune Evasion by Herpes Simplex Viruses

Written By

Angello R. Retamal-Díaz, Eduardo Tognarelli, Alexis M. Kalergis, Susan M. Bueno and Pablo A. González

Submitted: November 19th, 2015 Reviewed: May 6th, 2016 Published: September 7th, 2016

DOI: 10.5772/64128

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Infection with herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) is extremely frequent in the human population, as well as recurrent reactivations due to lifelong infection. Infection and persistence of HSVs within healthy individuals likely results as a consequence of numerous molecular determinants evolved by these pathogens to escape both immediate and long-term host antiviral mechanisms. Indeed, HSVs harbor an arsenal of proteins that confer them stealth by negatively modulating immune function. Consequently, these viruses perpetuate within the host, altogether silently shedding onto other individuals. In this chapter, we discuss HSV determinants that interfere with cellular antiviral factors, as well as viral determinants that hamper innate and adaptive immune components intended to control such microbes. The identification of HSV evasion molecules that modulate the immune system, as well as the understanding of their mechanisms of action, should facilitate the design of novel prophylactic and therapeutic strategies to overcome infection and disease elicited by these viruses. This chapter is intended to provide an overview of the evasion mechanisms evolved by herpes simplex viruses to escape numerous host antiviral mediators.


  • immune evasion
  • innate immunity
  • adaptive immunity
  • antiviral response

1. Introduction

Herpes simplex viruses (HSVs, HSV-1 and HSV-2) are extremely prevalent in the human population with virtually half of the world inhabitants infected with HSV-1 [1] and nearly 500 million with HSV-2 [2]. Novel infections with HSVs are estimated at a rate of dozens of millions individuals per year [3]. Importantly, the prevalence of HSV infection significantly varies depending on the geographical location of individuals, sex, and ethnicity [37]. While primary HSV-1 infection is well known for its pathological effects in the oro-facial area, where it mainly produces lesions in the mouth, it is also responsible for most cases of infectious blindness in developed countries [821]. On the other hand, HSV-2 is widely recognized as an important contributor to neonatal encephalitis and, most importantly, the main cause of genital ulcers in the world [821]. Nevertheless, despite this latter association between HSV-2 and genital infection, HSV-1 is at present the main cause of primary genital infection [9, 12]. This apparent paradox may be explained by the fact that HSV-2 recurs significantly more frequently in the genitalia than HSV-1, while the opposite occurs for the oro-facial area [22]. Such differences may be accounted by disparities in the capacity of each of these viruses to establish latency in the sacral and trigeminal ganglia [23], although another study proposes that this is not the case [24]. Regardless of differences in neuron infection or reactivation capacity from these sites, overall HSV-2 is isolated more frequently than HSV-1 in the genitalia during the lifespan of an individual [23]. Importantly, HSV-2 is considered at present a meaningful contributor to the fueling of human immunodeficiency virus (HIV) infection in the world, and is discussed in detail below [22, 2527].

Besides viral encephalitis in neonates, as well as oro-facial and genital lesions, HSV-1 and HSV-2 are also responsible for numerous other diseases in humans, such as adult encephalitis, herpetic keratitis, conjunctivitis, and skin lesions, within many other clinical manifestations [4]. The variety of pathologies produced by HSVs and tissues affected may be due, at least partially, to the wide distribution of their receptors, which are virtually present on all cells of the body [28]. Noteworthy, such clinical outcomes can occur indistinguishably both in immunocompetent and immunocompromised individuals and are likely a result of the evolution and selection of HSV determinants that interfere with early antiviral cellular mechanisms, innate- and adaptive-immune components. Noteworthy, HSV genomes encode numerous gene products (at least 70), which likely warrants these microbes a collection of proteins with immune evasion properties [29]. Below, we discuss several of these viral determinants, as well as how they interfere with host antiviral processes.


2. Herpes simplex viruses escape early antiviral responses

2.1. Interference with host pathogen recognition receptors

Upon encounter with foreign molecules or danger elements, host immune and nonimmune cells may sense such stimuli and initiate intracellular-activating signaling pathways that lead to their alertness and that of surrounding cells. Importantly, complex host organisms have evolved as specialized receptors for recognizing these microbial elements or self-induced danger molecules during abnormal processes elicited by these microbes. Such receptors are usually termed pattern recognition receptors (PRRs) [30]. PRRs can recognize pathogen-associated molecular patterns (PAMPs), which consist on a diverse collection of biomolecules derived from microbial elements, such as proteins, lipids, carbohydrates, or particular arrangements or sequences of nucleic acids, within others [31]. Alternatively, these receptors can also detect danger signals released by host cells undergoing stress circumstances, such as those that might be elicited by virus replication. These latter danger signals are termed damage-associated molecular patterns (DAMPs) [32]. Upon engaging PAMPs and DAMPs, PRRs elicit intracellular signals that result in the transcription and translation of antiviral genes, as well as the expression of soluble and membrane-bound molecules. Timely and robust detection of PAMPs and DAMPs by the host after viral infection can lead to effective microbe control and promote the establishment of protective immunity [31, 33].

Upon exposure to HSVs, the main host cells susceptible to infection are likely live epithelial cells. These cells are largely present at the interphase with the exterior world and abundantly present in the mucosae and to a lesser extent, in microscopic skin lesions. As most nonimmune cells in the organism, these cells express the main HSV receptor, nectin-1 [28]. After attaching and binding to their receptors, the membranes of these viruses undergo a fusion process with that of the host cell to release the viral capsid and surrounding tegument proteins within the cytoplasm [34]. While the tegument proteins remain in the cytoplasm, where they exert numerous cellular modulatory effects, the capsid associates to microtubules and travels to the outer nuclear membrane, where it binds to host nuclear pore proteins and releases the viral DNA into the nucleus [35]. It has been described that at this stage host molecular sensors can sense HSV-2 determinants (Table 1). Interferon-gamma inducible-16 (IFI-16) detects the HSV genome and subsequently induce IL-6 and IFN-α production in primary vaginal epithelial cells [3638]. On the other hand, the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS), a recently described DNA sensor, has also been reported to detect HSV-derived nucleic acids and lead to IFN-α and IFN-β secretion by both immune cells, such as macrophages and dendritic cells (DCs), and nonimmune cells, such as fibroblasts [39]. Importantly, animals that lack cGAS are vulnerable to HSV, while functional cGAS leads to T-cell activation and antibody production by B cells [40]. Although HSVs seem to be unable to interfere with cGAS sensing, other herpesviruses (gammaherpesviruses) have been recently described to encode viral determinants that impair the function of this molecule, namely, ORF52 of Kaposi’s sarcoma herpesvirus [41]. Interestingly, a recent study suggests that IFI16 and cGAS work cooperatively to sense HSV, as silencing one or both proteins significantly decreases virus detection. More specifically, cGAS was shown to directly interact with IFI-16 in fibroblasts and to promote the stability of the latter [39]. Noteworthy, both sensors IFI-16 and cGAS signal intracellularly through interferon regulatory factor-3 (IRF3) and again silencing either sensor inhibits the activation of IRF3 in response to HSV DNA [42]. Further, the importance of IFI-16 in limiting HSV infection has been recently shown in vivo. Knocking down IFI-16 led to the loss of IFN-α production, as well as reduced viral control in the corneal epithelium [38]. While the mechanism by which IFI-16 recognizes HSV DNA remains somewhat unclear, a recent study using chromatin immunoprecipitation (ChIP) found that IFI-16 binds to HSV promoter sequences and that reducing the levels of IFI-16 expression resulted in host proteins binding to these elements, ultimately favoring viral gene transcription [43].

Viral determinant involved Outcome Mechanism References
IFI-16 Nuclear virus DNA HSV sensed. IL-6, IFN-α
IFI-16 binds to viral promoters [3638, 43]
cGAS Nuclear virus DNA HSV sensed. IFN-α, IFN-β
cGAS binds directly to B-DNA [39]
DAI Cytosolic virus DNA HSV sensed. IL-6, IFN-β
DAI binds directly to B-DNA [36]
MDA5 vhs Unable to sense viral nucleic
vhs protein reduces host
protein expression
[44, 45]
RIG-1 vhs Unable to sense viral nucleic
vhs protein reduces host
protein expression
[44, 45]
TLR-9 Cytosolic virus DNA HSV sensed. IL-6, IL-12, type-I
IFN secretion
Undetermined [36, 46]
PKR γ34.5 and US11 Impaired viral dsRNA
Viral proteins block eIF2-α
TLR7 Undetermined HSV sensed Undetermined [58]
TLR3 Virus or virus-induced
host nucleic acids
HSV sensed. IL-6, TNF-α
TLR-3 signals through IRF3 [6365]
ανβ3 ICP0 Inhibited detection of viral
ICP0 blocks type-I IFN
transcription and virus targeting
to degradation
TLR2 dUTPase HSV sensed. IL-6, IL-8, IL-10,
IL-12, and TNF-α secretion
Undetermined [77]
ICP0 ICP0 reduces IL-1β secretion Inflammasome directed to
proteasome degradation in
timely manner
[32, 43]

Table 1.

HSV evasion of host virus sensing.

IFI-16 (gamma-interferon-inducible protein); cGAS (cyclic GMP-AMP synthase); DAI (DNA-dependent activator of Interferon-regulatory factor); MDA5 (melanoma differentiation-associated protein 5); vhs (virion host shutoff protein); RIG-1 (retinoic acid-inducible gene 1); TLR-2, -7, -9 (Toll-like receptor-2, -7 and -9); PKR (protein kinase RNA-activated); ανβ3 (integrin alphaVbeta3); γ34.5 (late gene gamma 34.5, ICP34.5); US11 (short unique region 11); IRF3 (interferon regulatory factor 3); ICP0 (infected cell protein 0); IL-1β, -6, -8, -10,-12 (interleukin-1β, -6, -8, -10, and, -12); IFN-α/β (interferon alpha and beta); TNF-α (tumor necrosis factor-alpha).

Another host DNA sensor capable of detecting HSV genetic material is DNA-dependent activator of interferon (DAI), which is expressed in primary vaginal epithelial cells and leads to cytokine expression by these cells, such as IL-6 and IFN-β after virus exposure (Table 1) [36]. Surprisingly, DAI is expressed in the cytoplasm, suggesting that HSV DNA likely escapes or leaks from the nucleus, or capsids into the cytoplasm where it reaches this sensor.

Other nucleic acid detectors intended to perceive microbe-derived genetic material are retinoic acid-inducible gene-1 (RIG-I) and melanoma differentiation-associated protein-5 (MDA5) (Table 1) [44]. Unlike the other DNA sensors discussed above, the functions of RIG-I and MDA5 are hampered by HSV, namely, by the viral protein designated virion host shutoff protein (vhs). The vhs has been shown to specifically reduce the expression RIG-I and MDA5, as a mechanism to interfere with downstream signaling events carried out by these detectors, which are intended to alert neighboring and immune cells when viral elements are present (Table 1) [45]. Similar to DAI, RIG-I and MDA5 are also present in the cytoplasm of cells, which indicates that HSV DNA likely reaches this compartment during the infectious cycle [36].

Another PRR that also recognizes viral DNA is Toll-like receptor-9 (TLR9), which is mainly known for its role in sensing bacterial-derived nucleic acids, namely, CpG-oligodeoxynucleotides (CpG ODNs). TLR9, which is expressed both by immune and nonimmune cells, has been shown to detect HSV elements and produce IL-6, IL-12, and type-I IFN, within others (Table 1) [36, 46]. Although TLR9 is capable of sensing HSV, its function seems nonessential for animal survival upon viral challenge. Indeed, TLR9 knockout mice survive central nervous system (CNS) infection, although they do display increased viral loads in the brain, when compared to wild-type mice [47]. Remarkably, animals treated with TLR9 agonists, such as CpG ODNs previous to infection, display significantly reduced viral loads and inflammatory cytokines in the brain (CCL2, IL-6, and CCL5) [48]. A similar protective effect has been observed for CpG ODNs in mice that were treated locally with such stimulators and then challenged in the genitalia with HSV [4952]. These results suggest that engaging TLR9 receptors, or promoting their signaling pathways may be a promising strategy for preventing HSV burden in the host.

Although the genomes of HSVs are composed of DNA, these viruses produce viral RNA molecules during their infectious cycles that are generated as a consequence of transcription. These RNA molecules are then processed into mRNAs and miRNAs that may form tridimensional structures, which could be recognized by host sensors. One such sensor is host protein kinase R (PKR), which can detect double-stranded RNA molecules and mediate downstream signaling events that lead to limited virus replication by favoring NF-kB activation and cytokine release, while altogether inhibiting protein synthesis through the phosphorylation of the host translation initiation factor 2-alpha (eIF2α), which ultimately can promote cell death (apoptosis) [53]. To date, numerous studies have demonstrated that HSV can indeed interfere with PKR function both in vitro and in vivo in such a way to promote their infectious cycles (Table 1) [54, 55]. Furthermore, interference with the capacity of PKR to phosphorylate eIF2α has been shown to be mediated by the HSV proteins γ34.5 and US11, which allows viral protein synthesis to occur efficiently within infected cells [56, 57].

Another nucleic acid-sensing molecule capable of recognizing double-stranded RNA species produced during viral infection is TLR7, although to date this particular receptor has not been described to sense any particular form of nucleic acid generated during HSV infection (Table 1). Nevertheless, some studies report that the application of TLR7 agonists, such as imiquimod to experimental animals can significantly decrease HSV infection and disease after virus challenge [58]. Such findings have led to the assessment of imiquimod as a therapeutic approach to treat HSV infection in humans, particularly for combating HSV isolates that are resistant to acyclovir, which are commonly found in immunocompromised patients [5961]. For example, a recent report described successful treatment of hypertrophic genital herpes in a HIV-positive patient after using 5% imiquimod applied in a topical manner after repeated failure to resolve the symptoms in the patient with oral and intravenous antivirals [62]. Although the results obtained till date on this type of approach have been promising, the mechanism of action of imiquimod over HSV remains unclear, as both interferon-dependent and interferon-independent mechanisms seem to play favorable roles against viral infection, which may further be mediated by processes that are independent of TLR engagement [60].

Lastly, another host nucleic acid sensor is TLR3, which is mainly known to recognize double-stranded RNA [63]. Importantly, TLR3 has been reported to play relevant roles in HSV disease, although its participation during infection has mainly been inferred by its deficiency (Table 1). For instance, TLR3−/− mice display severe HSV burden within the CNS after infection, which is thought to be mediated by astrocyte infection. Indeed, the expression of TLR3 in such cells increases the control of HSV infection early after virus entry into the CNS, seemingly by inducing type-I IFN responses [64]. Such interferon response would be mediated by TLR3-induced NF-kB activation in astrocytes and a posterior increase in the expression of IL-6 and TNF-α, which likely play antiviral functions in this tissue [65]. A relevant role for TLR3 in humans was initially proposed for infants, but has now extended onto adults thanks to recent studies performed on individuals that carry mutations in this receptor that negatively modulate its function. For instance, individuals harboring mutations in TLR3 have been reported to display a history of HSV encephalitis [6669]. Additionally, a direct relationship between downstream TLR3 signaling, TLR3 defects, and virus burden in astrocytes has been shown with ex vivo differentiated neurons, astrocytes, and oligodendrocytes obtained from patients that display TLR3 deficiencies. Cell cultures derived from these individuals and infected with HSV show reduced virus control in vitro, as compared to cells obtained from controls, which secreted more interferon [70]. Furthermore, HSV-susceptible individuals have also been reported to display mutations in proteins that are involved in the downstream signaling of TLR3, such as in IRF3 [69, 71, 72]. As with TLR9 and TLR7, agonists for TLR3 such as polyI:C have also been shown to reduce viral burden when applied in the genitalia or intraperitoneally previous to a genital challenge with HSV [73]. Overall, these results highlight an important role for TLR3 in HSV encephalitis, altogether proposing potential new treatment alternatives for reducing HSV burden in the brain and other tissues.

While HSV-derived nucleic acids are perceived by numerous host sensors in infected cells, relatively few HSV proteins have been described to be detected by the host (Table 1). Integrin ανβ3, which has seldom been recognized as a PRR was recently described as a sensor for HSV, which is negatively modulated by these viruses. Furthermore, the HSV protein ICP0 has been proposed to be responsible for blocking the signaling events triggered by integrin ανβ3 within infected cells, which otherwise would lead to NF-kB activation, type-I IFN transcription, and the direction of virus particles to cholesterol-rich microdomains that are targeted for degradation [7476].

An HSV protein that is successfully detected by host sensors is the viral dUTPase, which has been shown to be sensed by TLR2 in DCs and leads to IL-6, IL-8, IL-10, IL-12, and TNF-α secretion (Table 1) [77]. Interestingly, TLR2 has also been reported to recognize other HSV elements, with partial modulation by TLR9 [78]. Noteworthy, experiments performed with TLR2−/− knockout mice showed that these animals displayed increased survival rates, as compared to wild-type animals after challenge with HSV, which suggests a potentially negative role for this receptor in disease severity. Yet the knockout animals had similar levels of viral loads in their tissues, as control animals [79]. Remarkably, microglia cells obtained from TLR2−/− mice have been shown to produce reduced levels of reactive oxygen species (ROS) after HSV infection, when compared to control cultures, which might result in decreased cellular oxidative toxicity to neurons and positively impact on their viability [80].

The inflammasome is a host multiprotein complex harboring the cytoplasmatic sensors NLRP3, AIM2, and IFI-16, which has been described to sense HSV constituents, although its activation is negatively modulated during infection (Table 1) [32]. While IFI-16 and NLRP3 are activated early after HSV infection with consequent IL-1β release, at later time points IFI-16 has been reported to be directed to the proteasome by the viral protein ICP0 [32, 43]. This observation implies that the overall function of this sensor complex is likely hampered by HSV and thus limited at properly alerting other cells of an ongoing viral infection.

Taken together, HSVs seem to be sensed by host cells mainly at the nucleic acid level rather than protein level. This observation is quite surprising considering that HSVs encode numerous gene products within their genomes (>70 ORFs) and at least 11 surface glycoproteins. This stealth attribute might be explained within others by the ability of these viruses to interfere with downstream signaling events mediated by PRRs, as discussed in detail below. Additionally, their apparent invisibility might also be a consequence of the viruses’ capacity to interfere with host translation of mRNA transcripts that encode soluble and membrane-bound mediators required for cell alertness after infection and also communicating infection onto other cells. Indeed, the HSV-1 and HSV-2 vhs proteins efficiently inhibit the translation of host mRNAs by promoting their degradation directly through their ribonuclease activity [81]. Importantly, increased degradation of host transcripts over viral mRNAs would be mediated by the spatial-temporal regulation of vhs expression in infected cells, as vhs proteins are delivered together with the tegument immediately after infection, then poorly expressed during viral replication and then abundantly produced immediately before virus packaging and exit [82]. More recently, vhs proteins have been reported to interfere with stress granule formation within infected cells, thus counteracting host antiviral stress responses that are usually elicited early after infection [83].

2.2. Negative modulation of interferon pathways

An effective mechanism by which host cells restrict viral replication is due to interferons, soluble proteins, that induce antiviral responses both in cells that secrete these mediators as well as neighboring cells [84]. While type-I interferons (IFN-α, IFN-β, and IFN-ε, within others) are usually secreted early after microbe infection by diverse cell types, type-II interferons (IFN-γ) are secreted by specific subsets of immune cells at later stages of infection. On the other hand, type-III interferons (IFN-λ1, IFN-λ2, and IFN-λ3) have similar effects and kinetics than type-I IFNs, although they are mostly restricted to epithelial cells [63, 8589]. While type-I and type-III IFNs induce multiple antiviral effects in most host cells, type-II IFNs play more regulatory roles, mainly in immune cells.

Target host molecule Viral
Outcome Mechanism References
IRF3 function ICP0 Inhibits type-I IFN expression ICP0 RING finger motif inhibits
IRF3-mediated transcription of interferon stimulating genes
[90, 91]
Us3 Decreases IFN-β production Viral Ser/Thr kinase activity hyperphosphorylates IRF3, blocking its dimerization and nuclear translocation [92]
UL36 Inhibits IFN-β transcription UL36 de-ubiquitinates TRAF3, which inhibits stimuli-induced dimerization of IRF3 [94]
IRF3, NF-kB VP16 Inhibits IFN-β
Inhibits NF-kB activation and blocks the recruitment of IRF3 co-activator CBP [93]
STAT-1 function ICP27 Neutralizes
expression of IFN-I
Interferes with nuclear accumulation of STAT-1, impairing with the activity of this transcription factor [96]
STAT-2 function Undetermined, vhs (partially) Interferes with IFN-I signaling Partially attributed to vhs-mediated
reduction of transcription factor activity
[97, 98]
Undetermined, vhs (partially) Interferes with IFN-I signaling Partially attributed to vhs-mediated
reduction of transcription factor activity
[97, 98]
IFN-ε, IFN-α Undetermined Reduces viral dissemination and reactivation Activates TLR signaling through unknown viral agonist [99102]
Undetermined Induces IFN-β expression. Prevents keratinocyte and neural infection Unknown viral antigen activation of
TLR3 and Jak-STAT signaling
IL-28A function Undetermined Prevents neural
Unknown viral antigen. TLR-mediated activation of IRF7 [105]

Table 2.

HSV interference with host intracellular signaling.

IRF3 (interferon regulatory factor 3); NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells); STAT-1, -2 (signal transducer and activator of transcription-1, -2); Jak-1 (Janus kinase 1); IFN-ε, IFN-α (interferon-epsilon, -alpha); IL-28A, -29 (interleukin-28A, -29); UL36 (long unique region 36); VP16 (viral protein 16); ICP27 (infected cell protein 27); TRAF3 (TNF receptor-associated factor 3); CBP (CREB-binding protein).

HSVs encode numerous virulence factors that negatively modulate the induction of host interferon responses and their effects, some of which were briefly discussed above (Table 2). For instance, HSVs interfere with PRR-mediated intracellular signaling events that otherwise would lead to the transcription of IFN-I. Such effect has been reported to be mediated by HSV proteins such as ICP0, which interferes with IRF3 to block the transcription of target genes, namely, type-I IFNs [90, 91]. On the other hand, the HSV Ser/Thr kinase US3 has also been shown to interfere with signaling mediated by this transcription factor by carrying out its hyperphosphorylation, which blocks its dimerization, nuclear translocation, and hampers IFN-β production [92]. Additionally, the tegument protein VP16 has also been described to abrogate IFN-β expression by inhibiting IRF3 and NF-kB activation, specifically by impairing the recruitment of the coactivator CBP (CREB binding protein) and not necessarily through a mechanism that affects IRF3 dimerization, nuclear translocation, or its DNA binding activity [93]. Finally, IFN-β transcription has also been reported to be inhibited by the viral ubiquitin-specific protease UL36, which de-ubiquitinates TRAF3 (TNF receptor-associated factor-3) and consequently inhibits stimuli-induced IRF3 dimerization [94]. Interference with signaling events that lead to type-I IFN secretion has also been evidenced in vivo by the observation that only reduced amounts of IFN-α and IFN-β are produced in the genital tract after HSV infection [90, 95]. Negative modulation of the interferon pathway is summarized in Table 2.

Although small amounts of type-I IFNs are produced during HSV infection, the effects of these meager amounts of interferons are neutralized by HSVs, thanks to the activity of the viral protein ICP27, which interferes with STAT signaling (signal transducer and activator of transcription), which is located downstream of IFN-I receptors. Indeed, HSV ICP27 interfere with nuclear accumulation of STAT-1 and impair the function of this transcription factor [96]. Additionally, other transducers of IFN-I signaling, such as STAT-2 and JAK1 (Janus Kinase), have also been reported to be reduced in HSV-infected cells and experiments with mutant viruses suggest that these effects would be mediated, at least partially by virally encoded vhs [97]. Additional viral and nonviral determinants released by HSV-infected cells have been suggested to interfere with IFN-I signaling, although their nature has not been fully characterized [98]. Although IFN-ε signals through similar receptors than IFN-α and IFN-β, this recently described mediator is constitutively expressed by epithelial cells in the genitalia and would likely play a role against HSV burden [99101]. However, the mechanism by which IFN-ε would limit HSV infection remains to be determined. Consistent with an important role for type-I IFNs in response to HSV infection, treatments with TLR agonists, such as imiquimod, poly(I:C), or CpG-ODNs, discussed above all induce strong interferon responses [51, 52, 5861, 73]. Additionally, application of topical IFN-α has been shown to significantly reduce viral dissemination, as well as the frequency of viral recurrences in HSV-infected patients that manifest frequent genital viral reactivations [102]. The role of IFN-I in HSV infection is also evidenced in experiments assessing mice that lack the receptor for this molecule (IFNAR1 and IFNAR2c), which were inoculated in the footpads with the virus. These animals displayed reduced HSV control and systemic infection that affected multiple organs, although the disease was nonlethal [103].

At present, several studies seem to have identified a favorable role for type-II IFNs in HSV infection, as discussed in the following sections. Yet surprisingly, one study that evaluated infection in mice that had the IFN-II receptor deleted (IFNGR1 and IFNGR2) showed that these animals had comparable levels of virus than wild-type controls [103].

Unlike type-I IFNs, relatively few reports have documented a role for type-III IFNs in HSV infection. One such study has reported that IFN-λ1 (IL-29) induces the expression of several antiviral proteins in human keratinocytes. Furthermore, administration of this cytokine, previous to HSV infection induced IFN-β and prevented keratinocyte infection upon HSV challenge. Notably, the effect of this interferon depended on TLR3 expression, which was upregulated, and JAK-STAT activation [104]. Additionally, IFN-λ1 and IFN-λ2 (IL-28A) have also been reported to suppress HSV infection in human neurons (Table 2). Again, IFN-III was shown to induce TLR expression and elicit TLR-mediated antiviral pathways that involved IRF7 [105]. Noteworthy, the secretion of type-III IFNs in the vaginal mucosa has been suggested to be mainly mediated by DCs, although this has not been evaluated yet in the context of an HSV infection [106].

Taken together, HSVs have evolved multiple mechanisms to interfere with host interferon responses, from IFN transcription to IFN signaling. These evasion mechanisms, largely redundant, highlight the importance of this type of response in limiting HSV infection. Indeed, novel therapeutic strategies seem to share in common the induction of type-I IFNs, which should facilitate the identification of novel formulations that provide beneficial effects against these viruses.

2.3. HSV modulation of cell viability

Viruses utilize cells as substrates for replication and require, within others their translation machinery for synthesizing their proteins. Maximization of virion production is favored by extended cell survival and thus viruses have evolved molecular mechanisms to inhibit cell apoptosis. As discussed above, interference with programed cell death is achieved in part by the blockage of virus detection, but also thanks to viral determinants that directly hamper this cellular antiviral function. Cellular apoptosis can be mediated by two major pathways triggered either by intrinsic or extrinsic stimuli [107]. While the intrinsic pathway can be initiated by intracellular events that alter the redox state of the cells, damage the host DNA, or compromise mitochondrial integrity, within others, the extrinsic pathway can be elicited by the engagement of surface receptors, such as Fas [107]. HSVs have evolved molecular determinants that block both, intrinsic and extrinsic apoptosis signaling pathways in infected cells (Table 3). For instance, inhibition of apoptosis has been described to be mediated by the viral proteins US3, US5, and US12, each with unique inhibitory effects over the viability of the infected cells, either confronted or not to cytotoxic T cells [108]. More specifically, the HSV protein US3 has recently been described to mediate its antiapoptotic effects in epithelial cells, by interacting with programmed cell death protein 4 (PDCD4) and retaining it within the nucleus of infected cells [109]. HSV ICP10PK and UL14 would also harbor antiapoptotic effects in neurons and epithelial cells, although the mechanisms mediating these effects remain unknown [110, 111].

On the other hand, inhibition of apoptosis in HSV-infected cells by the extrinsic pathway has been suggested to occur by the sequestering of Fas ligand, which consequently would hamper Fas/FasL (CD95/CD95L) engagement, and thus block the capacity of T cells to mediate the killing of target cells [112]. Additionally, a recent study found that although some HSV-infected cells express Fas on their surface, HSVs can block Fas-mediated apoptosis by a mechanism that is independent of viral activation of NF-kB, as this transcription factor could be detected within the nucleus of infected cells [113]. Consistent with altered Fas/FasL function in HSV-infected cells, therapeutic application of soluble Fas ligand has been reported to ameliorate acute and recurrent herpetic stromal keratitis (HSK) in mice, by reducing inflammatory infiltration into the eye and decreasing eye neovascularization in primary and recurrent forms of HSK [114]. Interestingly, HSV glycoproteins gJ and gD have been proposed to mediate, at least partially the inhibition of Fas-mediated apoptosis [115, 116]. Paradoxically, gJ induces ROS within cells, which could trigger intrinsic pro-apoptotic stimuli. On the other hand, HSVs have been recently described to be able to suppress necroptosis in human cells as a mechanism to extend cell viability [117]. The viral proteins ICP6 and ICP10 have been recently described as the viral determinants that block necroptosis elicited by TNF in human cells [117]. The effects of HSV determinants over cell viability are summarized in Table 3.

Cell type Viral determinant  Outcome Mechanism References
Epithelial US3 Prevents apoptosis Acts retaining PDCD4
within the nucleus
[108, 109]
Fibroblast Us5 Prevents apoptosis Unclear. Inhibition of
caspase 3 activation
Fibroblast Us12 Prevents physiologic and CTL-induced apoptosis Unclear. Inhibition of
caspase 3 activation
Epithelial and neuronal ICP10PK and
Prevents apoptosis Unknown [110, 111]
Neuronal gD and gJ Prevents apoptosis Inhibits Fas-mediated pathway [115, 116]
Neuronal LAT Prevents cold shock-induced apoptosis Maintains high levels of
phosphorylated AKT in cells
Epithelial ICP6 and
Prevents necroptosis Blocks cell death elicited by TNF [117]
Dendritic cell Undetermined Induces cell death-related processes Unclear [118120]
Natural killer Undetermined Induces apoptosis Induction of Fas/FasL through infected macrophage expression [121]
Fibroblast ICP6 Induces necroptosis Interacts with host RIP-3 [122]

Table 3.

HSV modulation of cell death.

US3, 5, 12 (short unique region 3, 5, 12); ICP10PK (ICP10 serine-threonine protein kinase); UL14 (long unique region 14); gD, gJ (glycoprotein D, J); LAT (latency-associated transcript); AKT (protein kinase B); ICP6, 10 (infected cell protein 6, 10); CTL (cytotoxic T lymphocyte); PDCD4 (programmed cell death protein 4); RIP-3 (receptor-interacting protein kinase 3); TNF-α (tumor necrosis factor-alpha).

Contrarily to the observations discussed above, other studies have reported proapoptotic effects for HSV proteins, as well as pronecrotic effects. For instance, infection of murine and human dendritic cells with HSV induces apoptosis, but after the virus has negatively modulated some of their properties ([118120] and below). Additionally, HSV has also been described to induce apoptosis in natural killer cell (NK cells) upon their interaction with infected macrophages that express Fas/FasL [121]. On the other hand, HSVs have been described to induce necroptosis in mouse fibroblasts through the direct interaction of viral ICP6 with host RIP3 (receptor-interacting kinase 3) [122]. Importantly, an HSV virus with ICP6 deleted was unable to produce necrosis in HSV-infected cells and RIP3-/- mice displayed compromised control of HSV pathogenesis and replication [123].

Importantly, several reports have described that neuron infection with HSV does not lead to cell death, but rather extends their life. Indeed, lower levels of caspase-3 transcripts have been found in HSV-positive, rather than HSV-negative trigeminal ganglia and neurons [124]. Furthermore, HSV determinants such as the latency-associated transcript (LAT), which is mainly expressed within infected neurons has been reported to protect cells from cold-shock-induced apoptosis by maintaining high levels of phosphorylated protein kinase AKT within the cells [125].

Taken together, these studies highlight unique properties of HSV in their capacity to modulate cell viability in a cell-specific manner. While the viability of nonimmune cells that serve as a substrate for virus replication is extended by antiapoptotic viral determinants, immune cells are targeted for death in such a way to evade the immune system. Noteworthy, neurons which act as reservoirs for the virus are maintained viable during infection.

2.4. Soluble mediators secreted shortly after HSV infection

Despite the capacity of HSV to limit the cell’s capacity to sense viral components or transduce activating signals after virus detection, which otherwise could lead to optimal antiviral responses, cells infected with HSV nevertheless secrete numerous cytokines upon infection. Secretion of these cytokines might be promoted by host sensors that effectively detect HSV determinants or alternatively might result from virus-oriented immune modulation intended to promote infection and persistence [32]. Thus, to date it is unclear whether soluble mediators secreted by HSV-infected cells either contributes to virus control and spread or promotes the virus’ life cycle within the host.

Signaling events that lead to the secretion of soluble mediators after microbe or danger signal detection is frequently mediated by the nuclear factor NF-kB, which translocates from the cytoplasm to the nucleus to promote gene transcription [126]. Because of the importance of NF-kB in this process, HSV encode several determinants to dampen the activity of this transcription factor. For instance, the HSV US3 kinase has been reported to hyperphosphorylate NF-kB (p65) and impairs its translocation to the nucleus, interfering with IL-8 secretion [127]. On the other hand, the HSV UL42 protein, which encodes for a DNA polymerase processivity factor, also binds to p65/RelA and to p50/NF-kB1 (NF-kB1 forms) to negatively modulate their migration into the nucleus after stimulation with TNF-α [128]. HSV ICP0 has also been described to inhibit NF-kB activation mediated by TNF-α, by interacting similarly with p65/RelA and p50/NF-kB1 [129]. HSV VP16 similarly has been shown to interfere with NF-kB activation in human endothelial kidney cells [93]. Paradoxically, other studies have proposed that HSV infection can induce persistent NF-kB nuclear translocation, although without concomitant transactivation activity and in epithelial cells from the retina (retinoblastoma) [130, 131]. Importantly, blocking NF-kB nuclear translocation in these cells significantly reduced virus yield. Altogether, these studies demonstrate significant modulation of this important transcription factor by HSV determinants, which may result in different cellular outcomes depending on the cell type infected.

Although HSV negatively modulates NF-kB activation, HSV-infected cells can produce numerous soluble mediators. For instance, primary endometrial genital epithelial cells infected with HSV produce CCL2, IL-8, IL-6, and TNF-α [132]. On the other hand, samples from the cervical mucus of women infected with HSV show elevated amounts of CXCL9 [133]. The latter chemokine together with CXCL10 have been shown to participate in antiviral responses against HSV in CNS infection in the mouse model by recruiting NK and cytotoxic T cells to the infected tissue [134]. Other chemokines, such as CCL2, which are promoted by HSV infection, may play positive roles against the virus in ocular infection, as shown in mice; CCL2 knockout mice displayed significant viral infection and reduced inflammatory monocyte recruitment into the affected tissue [135]. On the contrary, blocking specific chemokines such as CXCL2 which is released by monocytes in response to HSV is thought to bring neutrophils into the infection site, which would promote unwanted damaging responses to the host, particularly neurons [136].

HSV also induces IL-6 in numerous cell types after infection, such as microglia, mast cells, and dendritic cells. Importantly, this cytokine shows protective effects in microglia, which seems to be mediated by STAT3; however, the details of the processes that converge toward its protective effects remain unresolved [137, 138]. Mast cells secrete IL-6 early after HSV infection, as well as TNF-α. Interestingly, these soluble mediators are not promoted by HSV directly in this case, but by soluble molecules secreted by keratinocytes infected with HSV [139]. Importantly, animals that lack IL-6 or TNF-α succumb to death after HSV infection, which indicates that these soluble molecules play positive antiviral effects for the host [139]. Nevertheless, other studies propose that this latter cytokine might play a negative role for the host, as treating animals with an anti-TNF-α antibody in combination with the antiviral valacyclovir significantly ameliorated the prognosis of HSV encephalitis [140]. On the other hand, before DCs are killed by HSV, these cells secrete IL-6 and numerous other cytokines [119].

Noteworthy, HSV has also been described to induce the secretion of cytokines and chemokines that could favor host infection by other sexually transmitted microbes, such as the human immunodeficiency virus [141]. Accumulating evidence indicates that infection with HSV-2 can increase host susceptibility up to fourfold to acquiring HIV [142145]. Additionally, coinfection with these pathogens augments the shedding of both viruses, likely worsening patient prognosis. Importantly, similar findings have been observed in the mouse model with HIV/HSV coinfections [146]. Such increase in the susceptibility of acquiring HIV in HSV-infected individuals would be mediated by numerous factors, such as the increased recruitment, to the infection site of cells that are targeted by HIV [147149]. Furthermore, cells infected with HSV secrete cytokines that reactivate latent HIV from infected cells [119, 150] and may augment the expression of surface ligands that promote HIV infection [151, 152]. Finally, HSV infection can downmodulate the expression of molecules that favor the neutralization and destruction of HIV [153].

A soluble mediator frequently associated with virus control and clearance is IFN-γ. This innate and adaptive immune cytokine is recurrently associated with increased protection against HSV in numerous HSV infection models and considered an important mediator in the mechanism of action of different prophylactic formulations [154157]. Importantly, in the absence of IFN-γ, T cells directed against HSV secrete alternative cytokines that are known to possess antiviral functions, yet they are not protective against genital infection [158]. Thus, IFN-γ seemingly plays an important role in eliciting protective immunity against HSV.

Taken together, HSVs elicit the secretion of cytokines and chemokines both by immune and nonimmune cells. Yet, whether these soluble mediators play favorable roles for the host or these viruses remains somewhat unknown and requires further examination. To date, only type-I IFNs and IFN-γ seem to play evident favorable roles against HSV.


3. Herpes simplex viruses interfere with innate immunity

3.1. Interference with complement function

Complement is an acellular component of innate immunity that recognizes foreign elements and subsequently undergoes a series of controlled molecular chain reactions that either culminate with the establishment of a protein pore-forming complex that attacks bilipid membranes or induce receptor-mediated engulfment by cells [159]. Importantly, formation of the pore complex can be promoted either directly by the recognition of microbial molecular patterns on the surface of the virus by complement components, or induced by the Fc portion of antibodies that bind to foreign elements.

To counteract the effect of the complement, HSVs utilize glycoprotein gC, which binds to C3b and blocks its activity by impairing antibody-induced complement activation (Table 4) [160, 161]. Inhibition of C3 impairs complement-mediated virus inactivation and the lysis of virus-infected cells. Furthermore, gC also binds to complement component C5 to block its downstream activities, such as immune cell chemoattraction and membrane attack complex formation (Table 4) [162, 163].

HSVs have also evolved molecular determinants that bind to complement components required for antibody-mediated complement activation, as discussed below. Thus, by interfering with complement components HSVs increase their viability in the mucosae and sera of infected patients, which favors the infection of target cells.

Innate immune process altered Viral determinant Outcome Mechanism References
Complement gC Inhibits antibody-mediated complement activation Acts as a receptor for complement component C3b [160, 161]
Complement gC Impairs chemoattraction and membrane attack complex formation Binds to complement component C5 hampering its catalytic activity and inhibiting downstream events [162, 163]
Natural killer gD Suppresses NK degranulation and cell-mediated lysis of infected cells CD112 downregulation leading to reduced DNAM-1 activity [168]
Natural killer Undetermined Decreases NK activation Reduces the surface expression of MICA, ULBP1, ULBP2 and ULBP3 [169171]
Natural killer Undetermined Induces cell apoptosis Induces Fas/FasL interactions
through infected macrophages
Natural killer T cells US3 Inhibition of antigen presentation to NKT cells Phosphorylation of KIF3A produces CD1d downregulation in infected

Table 4.

Evasion of innate immunity.

gC, gD (glycoprotein C, D); US3 (short unique region 3); C3b, C5 (complement component 3b, 5); NK (natural killer cell); CD112 (nectin-2); DNAM-1 (DNAX accessory molecule-1); MICA (MHC class I polypeptide-related sequence A); ULBP1, 2, and 3 (UL16 binding protein 1, 2 and 3); KIF3A (kinesin family member 3); CD1d (antigen-presenting glycoprotein CD1d).

3.2. Negative modulation of NK and NKT function

Besides complement, innate immunity is also composed of numerous cells, such as macrophages, neutrophils, mast cells, basophils, eosinophils, and innate lymphoid cells (ILCs), within others. Importantly, HSV modulates the function of some of these cells, notably NK (Table 4). NK cells usually play important roles in eliminating infected cells that have lost class I major histocompatibility complex molecules (MHC-I) on their surface, because of microbe interference. Although NK cells can directly sense HSV through TLR2 and have been reported to be activated by plasmacytoid dendritic cells that have contacted HSV, their function is nevertheless dampened by the virus [164167]. Indeed, gD has been shown to suppress DNAM-1-dependent NK-cell-mediated lysis of HSV-infected cells [168]. Furthermore, HSVs can dampen the surface expression of the NK-activating ligand MICA (MHC class I polypeptide-related sequence A) in infected cells, by retaining this molecule intracellularly [169, 170]. More recent studies have revealed that HSV can also interfere with the expression of additional NK-activating ligands, such as ULBP1, ULBP2, and ULBP3 [171]. Importantly, HSVs can induce apoptosis in NK cells through Fas/FasL interaction between NK cells and HSV-infected macrophages, thus eliciting their deletion upon infection [121]. Although there is abundant evidence for negative modulation of NK cells by HSV, the contribution of these cells to HSV pathology remains somewhat controversial as both, negative and positive roles have been described for this cell population during HSV infection [172, 173].

Another innate immune cell type directly affected by HSV is natural killer T cells (NKT cells) (Table 4). These cells recognize glycolipid antigens presented on CD1d molecules [174]. Importantly, cells infected with HSV display reduced expression of CD1d on their surface, as they are redirected by viral determinants to intracellular compartments [175, 176]. Redirection of CD1d from the cell surface is mediated by the phosphorylation of host KIF3A by the viral kinase US3 [177]. Interestingly, vaginal application of α-galactosyl-ceramide an NKT ligand is shown to activate and recruit NKT cells to the genital tissue and decrease the susceptibility to HSV infection [178]. Remarkably, a recent report showed that NKT cells can contribute at determining the magnitude and profile of HSV-specific IgG antibodies upon HSV infection. HSV-infected NKT-cell-deficient mice displayed reduced amounts of antiviral IgM and IgG antibodies, as compared to wild-type mice [179]. These results suggest that NKT cells play an important role against HSV and that these viruses have evolved molecular mechanisms to interfere with their function. Furthermore, activating NKT cells with glycolipids may serve as a strategy to promote robust antibody responses against these viruses.

3.3. HSV interfere with dendritic cell function

Dendritic cells are immune cells strategically positioned at the interphase of innate and adaptive immunity. They are specialized in sensing microbes and danger signals, and also in integrating these signals and transducing them onto other cells for modulating the immune response to antigens [180183]. Because DCs are key at connecting innate and adaptive immunity and clearing microbes, pathogens have evolved numerous immune evasion mechanisms to overcome their function [181, 184189]. Importantly, HSV has been shown to infect DCs and to modulate their function by altering their maturation and capacity to activate T cells (Table 5) [118, 119, 190]. Furthermore, HSV can negatively modulate the autophagosome within DCs and interfere with their antigen processing capacity. This process is mediated by the viral protein γ34.5, which blocks autophagosome maturation [191, 192]. On the other hand, HSV-2 protein ICP47 has been shown to specifically block the expression of particular alleles of MHC-I on the surface of human DCs, namely, HLA-C, potentially rendering these cells more susceptible to NK killing and reducing the spectrum of HSV-derived antigens presented by these cells [193]. Remarkably, HSV has been shown to suppress many functions of DCs via caveolin-1 (Cav-1) by studying these cells in the lungs. HSV-induced Cav-1 was shown to downregulate the expression of inducible nitric oxide synthase; indeed, Cav-1-deficient mice or enhancement of nitric oxide production in wild-type mice ameliorated virus elimination and reduced pathology after HSV infection [194]. Furthermore, such crosstalk may occur between nonvirally infected dermal dendritic cells phagocytizing HSV-infected epidermal Langerhans cells, which are the first dendritic cells to encounter HSV in the skin [195].

Adaptive immune cell affected Viral determinant Outcome Mechanism References
Dendritic cell Undetermined Altered DC maturation and capacity to activate T cells Undetermined [118, 119, 190]
Dendritic cell γ34.5 Interference with autophagosome function and hence antigen processing Blocks autophagosome maturation [191, 192]
Dendritic cell ICP47 Increased susceptibility to NK attack Blocks MCH expression
(HLA-C allele)
Dendritic cell HSV-induced Cav-1 Reduced virus elimination and increased pathology Downregulates the
expression of inducible nitric oxide synthase
Dendritic cell Undetermined Induces DC cell death Undetermined [118120]
Humoral gE Blocks antibody function
related to complement activation and
antigen phagocytosis
Binding to the Fc portion of antibodies. Competes
with C1q and FcγRs
[201, 202]
T cell ICP47 and US3 Reduced CTL recognition of infected cells and decreased
naïve T cell activation
Interferes with host
TAP protein, impairing
peptide-MHC complex presentation
[205, 206]
T cell gD, gB, gH, gI,
and gL
Reduction in T cell activation and function. Decreases IL-2 secretion Signals through HVEM. Alters CD3-dependent intracellular calcium signaling [208]
T cell US3 Impairs T-cell activation Interferes with TCR signaling. Blocks TRAF6 activity, altering LAT function [209]
T cell gD Promotes Treg cell function with increased IL-10 secretion.
Likely to alter CTL activity
Induces proliferation of T CD4+ FoxP3+(CD25+) cell subsets [213217]

Table 5.

Evasion of adaptive immunity.

γ34.5 (late gene gamma 34.5, ICP34.5); ICP47 (infected cell protein 47); Cav-1 (caveolin-1); gB, gD, gE, gH, gI, gL (glycoproteins B, D, E, H, I, L); US3 (short unique region 3); DC (dendritic cell); NK (natural killer cell); Treg (regulatory T cell); MHC (major histocompatibility complex); HLA-C (human major histocompatibility complex chain C); C1q (subcomponent of the C1 complex of the classical pathway of complement activation); FcγR (Fc gamma receptor); TAP (transporter associated with antigen processing); HVEM (herpesvirus entry mediator); IL-2 (interleukin 2); CD3 (cluster of differentiation 3); TCR (T-cell receptor); TRAF3 (TNF receptor-associated factor 3); LAT1 (linker for activation of T cells); FoxP3 (forkhead box P3 protein).

Importantly, experiments with animals depleted of DCs have shown that these cells are involved in neuron infection, as up to fivefold less latent virus can be found in the trigeminal ganglia of animals devoid of these cells [196]. Consistent with this notion, another study found that depletion of CD11c+ CD8α+ DCs reduced HSV latency in neurons after ocular infection and that Flt3L treatment, which increases the number of DCs in the tissues, enhanced virus infection of neurons [197]. These studies suggest that DCs may be used as Trojan horses by HSV to reach neurons or that the virus might manipulate these cells in such a way to gain access to the former. However, another study that assessed HSV infection through the footpad in the mouse model found that depletion of DCs was associated with increased viral loads in neurons [198].

Taken together, these studies evidence numerous evasion strategies evolved by HSV to alter the function of DCs and consequently innate and adaptive immunity (discussed below). Additionally, these viruses seem to have harnessed the mobile properties of DCs to spread onto other host cells and tissues, namely, neurons. The fact that HSVs ultimately induce DC apoptosis will likely interrupt the establishment of effective and robust immune responses against these viruses.


4. Herpes simplex viruses evade adaptive immunity

4.1. Interference with humoral immunity

Although natural infection with HSV elicits antiviral antibodies with in vitro neutralizing capacities, these responses seem largely insufficient in most individuals when it comes to limit HSV symptoms and virus shedding. This host antibody response is mostly directed to few surface viral antigens, mainly gD, gB, and, to a lesser extent, gC all of which are essential for virus entry, except for gC in HSV-2 [199]. For antibodies to exert effective antiviral activities they need not to be necessarily neutralizing, as antibodies can also elicit complement activation and immune complex-induced phagocytosis, thanks to their Fc portion [200]. However, HSVs have evolved molecular mechanisms to evade these antibody functions (Table 5). Notably, the HSV-encoded glycoprotein E (gE) can interfere with complement activation by directly binding to the Fc portion of antibodies and competing with complement component C1q [201, 202]. Indeed, gE functions as an IgG Fc receptor (FcγR) that binds the Fc domain of IgG antibodies and thus blocks their capacity to promote complement activation, altogether impeding phagocytosis by immune cells [202204]. Importantly, specific interference with anti-HSV antibodies and not other circulating antibodies is achieved, thanks to the relatively low affinity of gE for the Fc portion of antibodies; antibodies are stabilized on the virus surface only if the Fab portion of the antibody is also bound to a viral antigen by its antigen-binding region. Hence, HSV has evolved molecular determinants to persist within the host and shed onto others, despite the existence of virus-neutralizing antibodies. Such evasion mechanisms have led to difficulties in the development of prophylactic formulations against HSV, and is further discussed below.

4.2. Evasion of T cell immunity

T cells can recognize microbe-derived protein fragments presented on the surface of infected cells and destroy these cells to limit virus replication and shedding onto other tissues and organisms. However, HSV encode molecular determinants that interfere with viral antigen presentation to T cells, namely, with MHC-I presentation, and thus the virus can hamper T-cell recognition of infected cells. HSVs interfere with the presentation of viral antigens by blocking the function of host TAP protein (transporter associated with antigen processing), which translocates self- and foreign peptides from the cytoplasm into the rough endoplasmatic reticulum for peptide loading onto MHC-I molecules (Table 5); TAP inhibition is mediated by the HSV protein ICP47 [205] and the US3 kinase [206]. Reduced peptide/MHC (pMHC) complexes on the surface of infected cells dramatically reduces the chances of cytotoxic T cells detecting HSV-infected cells, as well as the capacity of HSV-infected professional antigen presenting cells to activate naïve T cells.

Furthermore, additional mechanisms exist by which HSVs can negatively modulate the activation and proliferation of T cells (Table 5). For instance, the viral glycoprotein D binds to HVEM (herpesvirus entry mediator) on the surface of immune cells, which is a receptor belonging to the TNF-receptor superfamily and whose intracellular signaling mechanisms depends within others on the engagement of its different ligands and their orientation (cis vs. trans) [207]. gD binding to the cell surface of T cells has shown to alter calcium signaling within T cells after CD3 engagement, likely by interfering with the capacity of T-cell receptor to appropriately transduce intracellular signals that lead to suitable activation and function of these cells [208]. For instance, Jurkat T cells cultured with HSV and an activating CD3 antibody exhibit hampered IL-2 secretion [208]. A similar effect was observed with other HSV glycoproteins, namely, gB, gH, gI, and gL in the same study [208]. A recent report suggests that impaired T-cell activation would also be mediated by HSV Us3 protein interference with T-cell receptor signaling, specifically by altering linker for activation of T cells (LAT1) within these cells [209]. Importantly, infection of T cells (other than Jurkat cells) requires the presence of antigen-presenting cells for efficient virus transfer, a process termed virological synapse. Indeed, primary cultures of T cells incubated with HSV alone are only infected at very low frequencies, while adding fibroblasts significantly enhances the formation of virological synapses that culminate in a substantial increase in the number of T cells infected with these viruses [210]. Importantly, HSV has been described to lead to T-cell apoptosis [211].

T cells can carry out numerous functions depending on their phenotype. While cytotoxic T cells are specialized in killing microbe-infected cells, regulatory T cells (Tregs) are specialized within others in controlling the magnitude of the immune response to antigens [212]. In this regard, HSV seems to promote the proliferation of regulatory T cells through the binding of gD to HVEM receptors on the cell surface to promote the secretion of signature cytokines attributed to these cells, such as IL-10 (Table 5) [213216]. The promotion of Tregs might alter the activity of cytotoxic T cells intended to control the virus [213, 217]. Consistent with a negative role for Tregs in HSV infection, protection elicited against this virus in an animal model with previous immunization correlates with relatively low numbers of Tregs [218]. Nevertheless, another study proposes that deletion of Tregs in HSV-infected animals interferes with the migration of immune cells to the site of infection, negatively affecting the survival of infected animals [219]. Thus, further studies are needed to determine the contribution of Tregs in HSV infection.

4.3. Past and present vaccine attempts

Availability of an effective vaccine against HSV would be an important public health advance, mainly because individuals with genital herpes display increased susceptibility to acquire HIV [141145]. Importantly, previous efforts invested on the development of vaccines against HSV have concentrated on subunit approaches consisting mainly on one viral glycoprotein, namely, gD (Table 6) ([220], Glycoprotein gD is conserved within HSV serotypes and plays a key role during cell infection [221]. Furthermore, this viral protein harbors epitopes for CD4+ T cells [222], CD8+ T cells [223], and neutralizing antibodies [224] and is immunodominant as evidenced by clinical data showing that the majority of HSV-infected individuals have neutralizing antibodies against this protein [199]. Regretfully, this insisted strategy, which combines gD with adjuvants, recently failed in a phase 3 clinical trial; indeed, the formulation failed at reducing both HSV-2 infection and minimizing the shedding of the virus [225, 226]. Remarkably, the formulation tested in this and previous clinical trials induced anti-gD neutralizing antibodies in the vaccinated, as well as T CD4+ cells [220, 227230]. However, the magnitude of these responses may have been too weak for significant protection against HSV-2 after exposure [199, 228, 231, 232]. Unexpectedly, the vaccine provided 35% cross-protection against HSV-1 infection and 58% cross-protection against HSV-1 disease [227]. An important concern that arose from these results was whether the current animal models used to assess the efficacy of new HSV vaccines satisfactorily recapitulate what occurs in humans. It is also unclear whether the amount and/or quality of neutralizing antibodies elicited against HSV and T cells produced by vaccine formulations, such as the glycoprotein D/AS04 vaccine, play any relevant role in protection against HSV-2; furthermore, whether previously considered correlates of protection as anti-gD antibodies play any relevant role against this virus.

Importantly, a recent study suggests that anti-HSV antibodies, different from those directed against gD, might account for effective protection against HSV-2 after immunization with a discontinuous virus (Table 6). Indeed, animals immunized subcutaneously with a genotypically deleted gD virus elicited remarkable protection against genital and skin challenge with HSV-1 and HSV-2, which was mediated by antibodies. Noteworthy, the antibodies elicited by this attenuated HSV strain were poorly neutralizing and were mainly directed against gB [233]. A somewhat similar result was found in another study with an 0ΔNLS-attenuated HSV strain, which elicits antibodies against numerous virus-infected cell proteins (ICP) and gB, within others (Table 6) [234236]. Other attenuated HSV strains have also provided promising results in numerous mouse models and should move onto clinical trials, such as the HSV-2 dl5-29 strain, which has UL5 and UL29 deleted from its genome (Table 6) [237239]. Additional attenuated viral strains that confer significant protection against viral challenge are HSV strains that are impaired at infecting neurons, such as a gD mutant virus [240], HSV deleted at UL39 (ICP10ΔPK) [241], and HSV deleted at gE (Table 6) [242]. Regretfully, an HSV strain deleted at gH, which showed early promising results in animal models, was later shown to be ineffective in humans in a clinical trial [243]. Although most of these strategies elicit both anti-HSV antibodies and antiviral T cells, the main immune components involved in protection against HSV challenge remain unknown. Importantly, a recent study suggests that other animal models different from the guinea pig and the mouse infection model might be better suited for testing anti-HSV vaccine formulations. For instance, the cotton rat Sigmodon hispidus parallels well the results obtained with the D/AS04 vaccine in humans, both for HSV-1 and HSV-2 [244].

Formulation type Outcome Development stage References
Subunit protein gD plus adjuvant Alum and MPL (gD/AS04)  Induces T CD4+ and antibody
response. No clinical protection for shedding
and infection. 
Clinical phase 3 (completed)  [199, 220, 225233] 
Live attenuated, HSV-2 virus
with gH deletion (HSV-2 ΔgH) 
Safe and immunogenic, yet did not confer protection to HSV infection.  Clinical phase 2 (completed)  [243] 
Live attenuated, HSV-2 virus
with UL39 deletion (ICP10ΔPK) 
Induction of Th1 immunity  Clinical phase 2 (completed)  [241] 
Live attenuated, HSV-2 virus with
UL5 and UL29 deletions (ACAM529) 
Reduced disease, shedding, seroconversion, and latency  Preclinical stage  [237239] 
Live attenuated HSV-2 virus with
gD mutation (HSV-2-gD27) 
Protects from challenge and reduces viral load in neurons  Preclinical stage  [240] 
Live attenuated HSV-2 virus
with gD deletion (HSV-2 ΔgD−/+) 
Protects from genital and skin
challenge and blocks neuronal
infection. Antibody-mediated protection 
Preclinical stage  [233] 
Live attenuated, HSV-2 virus
with gE deletion (HSV-2 ΔgE2) 
Reduced infection and recurrence  Preclinical stage  [242] 
Live attenuated HSV- 2 virus
with ICP0 deletion (0ΔNLS) 
Antibody response against gB
and ICP viral proteins 
Preclinical stage  [234236] 

Table 6.

Past and present vaccine attempts against HSV.

AS04 (adjuvant system 04); MPL (monophosphoryl lipid A); gD, gE, gH (glycoprotein D, E, H); ICP10ΔPK (infected cell protein 10 lacking the PK domain); Th1 (T helper-1); UL5, UL29, UL39 (short unique region 5, 29, and 39); ICP0 (infected cell protein 0).

On the contrary to the evidence that suggests a role for antibodies in protection against HSV infection, a recent study proposes that effective protection against ocular HSV may be achieved by eliciting a robust T cell response alone. Indeed, humanized HLA transgenic animals vaccinated with T cell epitopes from different viral proteins identified in asymptomatic individuals and combined with adjuvant was shown to confer protection against ocular herpes [245247]. However, whether such results relate specifically to this type of herpetic disease or whether these T cells ultimately elicit an antibody response against HSV upon virus challenge remains unknown. Noteworthy, an important limitation of vaccine approaches that are based on one or few viral proteins is that only an oligoclonal set of T cells will be elicited, which may limit the effectiveness of formulation to a narrow set of individuals [248, 249].

Taken together, the HSV vaccine field has suffered an important failure and will need to revisit the immunobiology of its diseases. Importantly, the race for the development of novel prophylactic formulations against these viruses is reopened. While numerous groups aim at vaccine strategies that are based on defined viral proteins or viral epitopes, others propose attenuated HSV strains as an alternative for eliciting multiantigenic immune responses against these viruses. Regardless of the methods, a novel vaccine against HSV must guarantee safety for the immunocompetent and notably immunocompromised individuals. Remarkably, the lack of vaccines against HSV has encouraged considerable research in the field of microbicides, which might provide a strategy to prevent infection with these viruses [4].


5. Concluding remarks

Herpes simplex viruses have proven to be masters of immune evasion as they encode numerous molecular determinants that promote evasion of host sensing, signal transduction, cytokine secretion by immune and nonimmune cells, and, most importantly, interference with innate and adaptive immunity. These attributes likely explain the coexistence of HSV and humans since time immemorial and facilitates their high prevalence in the population [250]. Although HSV are seldom life threatening, the important economic burden they elicit with the diseases they produce and their association with HIV infection calls for the implementation of novel vaccines and improved treatments to stop their effects. Hopefully, lessons learned from past failed clinical trials will lead to novel strategies that will ultimately limit the impact of these viruses.



Authors are supported by the Millennium Institute on Immunology and Immunotherapy (n° P09/016-F) from the Iniciativa Científica Milenio (ICM, Millennium Scientific Initiative), as well as grants CRP-ICGEB CRP/CHI14-01, FONDECYT 1140011, FONDECYT 1140010, FONDECYT 11075060, FONDECYT 1100926, FONDECYT 1110518, FONDECYT 1110397. A.R.D. is a CONICYT fellow. A.M.K. is Chaire De La Région Pays De La Loire, Chercheur Etranger d’Excellence and a CDD-DR INSERM.


  1. 1. Looker, K.J., et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS ONE. 2015; 10: p. e0140765. DOI:10.1371/journal.pone.0140765.
  2. 2. Looker, K.J., et al. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS ONE. 2015; 10: p. e114989. DOI: 10.1371/journal.pone.0114989.
  3. 3. Looker, K.J., G.P. Garnett, and G.P. Schmid. Bulletin of the World Health Organization. 2008; 86: Pp. 805–812, A.
  4. 4. Suazo, P.A., et al. Herpes simplex virus 2 infection: molecular association with HIV and novel microbicides to prevent disease. Med Microbiol and Immunol. 2015; 204: p. 161–176. DOI: 10.1007/s00430-014-0358-x.
  5. 5. Yawn, B.P. and D. Gilden. The global epidemiology of herpes zoster. Neurology. 2013; 81: p. 928–930. DOI:10.1212/WNL.0b013e3182a3516e 10.1212.
  6. 6. Centers for Disease, C. and Prevention. Seroprevalence of herpes simplex virus type 2 among persons aged 14-49 years--United States, 2005–2008. Morb and Mortal Wkly Rep. 2010; 59: p. 456–459.
  7. 7. Dickson, N., et al. HSV-2 incidence by sex over four age periods to age 38 in a birth cohort. Sex Transm Infect. 2014; 90: p. 243–245. DOI:10.1136/sextrans-2013-051235 10.1136.
  8. 8. Roberts, C.M., J.R. Pfister, and S.J. Spear. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003; 30: p. 797–800. DOI: 10.1097/01.OLQ.0000092387.58746.C7.
  9. 9. Buxbaum, S., et al. Epidemiology of herpes simplex virus types 1 and 2 in Germany: what has changed? Med Microbiol Immunol. 2003; 192: p. 177–181. DOI:10.1007/s00430-003-0183.
  10. 10. Coyle, P.V., et al. Emergence of herpes simplex type 1 as the main cause of recurrent genital ulcerative disease in women in Northern Ireland. J Clin Virol. 2003; 27: p. 22–29.
  11. 11. Pereira, V.S., et al. Herpes simplex virus type 1 is the main cause of genital herpes in women of Natal, Brazil. Eur J Obstetrics Gynecol Reproductive Biol. 2012; 161: p. 190–193. DOI:10.1016/j.ejogrb.2011.12.006.
  12. 12. Xu, F., et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006; 296: p. 964–973. DOI:10.1001/jama.296.8.964 10.1001.
  13. 13. Horowitz, R., et al. Herpes simplex virus infection in a university health population: clinical manifestations, epidemiology, and implications. J Am Coll Health. 2011; 59: p. 69–74. DOI:10.1080/07448481.2010.483711.
  14. 14. Bernstein, D.I., et al. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis. 2013; 56: p. 344–351. DOI:10.1093/cid/cis891.
  15. 15. Samra, Z., E. Scherf, and M. Dan. Herpes simplex virus type 1 is the prevailing cause of genital herpes in the Tel Aviv area, Israel. Sex Transm Dis. 2003; 30: p. 794–796. DOI:10.1097/01.OLQ.0000079517.04451.79.
  16. 16. Manavi, K., A. McMillan, and M. Ogilvie. Herpes simplex virus type 1 remains the principal cause of initial anogenital herpes in Edinburgh, Scotland. Sex Transm Dis. 2004; 31: p. 322–324.
  17. 17. Kortekangas-Savolainen, O., et al. Epidemiology of genital herpes simplex virus type 1 and 2 infections in southwestern Finland during a 10-year period (2003–2012). Sex Transm Dis. 2014; 41: p. 268–271. DOI:10.1097/OLQ.0000000000000101.
  18. 18. Nieuwenhuis, R.F., et al. Importance of herpes simplex virus type-1 (HSV-1) in primary genital herpes. Act Derm Venereol. 2006; 86: p. 129–134. DOI:10.2340/00015555-0029.
  19. 19. Ryder, N., et al. Increasing role of herpes simplex virus type 1 in first-episode anogenital herpes in heterosexual women and younger men who have sex with men, 1992-2006. Sex Transm Infect. 2009; 85: p. 416–419. DOI:10.1136/sti.2008.033902 10.1136.
  20. 20. Farooq, A.V. and D. Shukla. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012; 57: p. 448–462. DOI:10.1016/j.survophthal.2012.01.005.
  21. 21. Kaye, S. and A. Choudhary. Herpes simplex keratitis. Prog Retin Eye Res. 2006; 25: p. 355–380. DOI:10.1016/j.preteyeres.2006.05.001.
  22. 22. Lafferty, W.E., et al. Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type. N Engl J Med. 1987; 316: p. 1444–1449. DOI: 10.1056/NEJM198706043162304.
  23. 23. Kaneko, H., et al. Evaluation of mixed infection cases with both herpes simplex virus types 1 and 2. J Med Virol. 2008; 80: p. 883–887. DOI:10.1002/jmv.21154.
  24. 24. Obara, Y., et al. Distribution of herpes simplex virus types 1 and 2 genomes in human spinal ganglia studied by PCR and in situ hybridization. J Med Virol. 1997; 52: p. 136–142.
  25. 25. Solomon, L., et al. Epidemiology of recurrent genital herpes simplex virus types 1 and 2. Sex Transm Infect. 2003; 79: p. 456–459.
  26. 26. Janier, M., et al. Virological, serological and epidemiological study of 255 consecutive cases of genital herpes in a sexually transmitted disease clinic of Paris (France): a prospective study. Int J STD AIDS. 2006; 17: p. 44–49. DOI: 10.1258/095646206775220531.
  27. 27. Benedetti, J., L. Corey, and R. Ashley. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med. 1994; 121: p. 847–854.
  28. 28. Krummenacher, C., et al. Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus. Virology. 2004; 322: p. 286–299. DOI:10.1016/j.virol.2004.02.005.
  29. 29. Grinde, B. Herpesviruses: latency and reactivation—viral strategies and host response. J Oral Microbiol. 2013; 5:22766. DOI:10.3402/jom.v5i0.22766.
  30. 30. Mogensen, T.H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009; 22: p. 240–273. DOI: 10.1128/CMR.00046-08.
  31. 31. Tang, D., et al. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012; 249: p. 158–175. DOI:10.1111/j.1600-065X.2012.01146.x.
  32. 32. Johnson, K.E., L. Chikoti, and B. Chandran. Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol. 2013; 87: p. 5005–5018. DOI:10.1128/JVI.00082-13.
  33. 33. Mogensen, T.H. and S.R. Paludan. Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev. 2001; 65: p. 131–150. DOI: 10.1128/MMBR.65.1.131-150.2001.
  34. 34. Owen, D.J., C.M. Crump, and S.C. Graham. Tegument assembly and secondary envelopment of alphaherpesviruses. Viruses. 2015; 7: p. 5084–5114. DOI:10.3390/v7092861.
  35. 35. Dohner, K., et al. Function of dynein and dynactin in herpes simplex virus capsid transport. Mol Biol Cell. 2002; 13: p. 2795–2809. DOI:10.1091/mbc.01-07-0348.
  36. 36. Triantafilou, K., D. Eryilmazlar, and M. Triantafilou. Herpes simplex virus 2-induced activation in vaginal cells involves Toll-like receptors 2 and 9 and DNA sensors DAI and IFI16. Am J Obstet Gynecol. 2014; 210: p. 122 e1–e10. DOI:10.1016/j.ajog.2013.09.034.
  37. 37. Dawson, M.J. and J.A. Trapani. The interferon-inducible autoantigen, IFI 16: localization to the nucleolus and identification of a DNA-binding domain. Biochem Biophys Res Commun. 1995; 214: p. 152–162. DOI:10.1006/bbrc.1995.2269.
  38. 38. Conrady, C.D., et al. Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16. Mucosal Immunol. 2012; 5: p. 173–183. DOI:10.1038/mi.2011.63.
  39. 39. Orzalli, M.H., et al. cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci U S A. 2015; 112: p. E1773–E1781. DOI: 10.1073/pnas.1424637112.
  40. 40. Li, X.D., et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013; 341: p. 1390–1394. DOI:10.1126/science.1244040.
  41. 41. Wu, J.J., et al. Inhibition of cGAS DNA Sensing by a herpesvirus virion protein. Cell Host Microbe. 2015; 18: p. 333–344. DOI:10.1016/j.chom.2015.07.015.
  42. 42. Unterholzner, L., et al. IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010; 11: p. 997–1004. DOI:10.1038/ni.1932.
  43. 43. Johnson, K.E., et al. IFI16 restricts HSV-1 replication by accumulating on the HSV-1 genome, repressing HSV-1 gene expression, and directly or indirectly modulating histone modifications. PLoS Pathog. 2014; 10: p. e1004503. DOI:10.1371/journal.ppat.1004503.
  44. 44. Reikine, S., J.B. Nguyen, and Y. Modis. Pattern recognition and signaling mechanisms of RIG-I and MDA5. Front Immunol. 2014; 5: p. 342. DOI: 10.3389/fimmu.2014.00342.
  45. 45. Yao, X.D. and K.L. Rosenthal. Herpes simplex virus type 2 virion host shutoff protein suppresses innate dsRNA antiviral pathways in human vaginal epithelial cells. J Gen Virol. 2011; 92: p. 1981–1993. DOI:10.1099/vir.0.030296-0.
  46. 46. Lund, J., et al. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003; 198: p. 513–520. DOI:10.1084/jem.20030162.
  47. 47. Krug, A., et al. Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood. 2004; 103: p. 1433–1437. DOI:10.1182/blood-2003-08-2674.
  48. 48. Boivin, N., et al. Modulation of TLR9 response in a mouse model of herpes simplex virus encephalitis. Antiviral Res. 2012; 96: p. 414–421. DOI:10.1016/j.antiviral.2012.09.022.
  49. 49. Ashkar, A.A., et al. Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2. J Virol. 2003; 77: p. 8948–8956.
  50. 50. Shen, H. and A. Iwasaki. A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide. J Clin Invest. 2006; 116: p. 2237–2243. DOI:10.1172/JCI28681.
  51. 51. Harandi, A.M., K. Eriksson, and J. Holmgren. A protective role of locally administered immunostimulatory CpG oligodeoxynucleotide in a mouse model of genital herpes infection. J Virol. 2003; 77: p. 953–962.
  52. 52. Pyles, R.B., et al. Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. J Virol. 2002; 76: p. 11387–11396.
  53. 53. Kang, R. and D. Tang. PKR-dependent inflammatory signals. Sci Signal. 2012; 5: p. pe47. DOI: 10.1126/scisignal.2003511.
  54. 54. Carr, D.J.J., et al. RNA-dependent protein kinase is required for alpha-1 interferon transgene-induced resistance to genital herpes simplex virus type 2. J Virol. 2005; 79: p. 9341–9345. DOI:10.1128/JVI.79.14.9341.
  55. 55. Leib, D.A., et al. Specific phenotypic restoration of an attenuated virus by knockout of a host resistance gene. Proc Natl Acad Sci U S A. 2000; 97: p. 6097–6101. DOI: 10.1073/pnas.100415697.
  56. 56. He, B., M. Gross, and B. Roizman. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1997; 94: p. 843–848.
  57. 57. Poppers, J., et al. Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein. J Virol. 2000; 74: p. 11215–11221.
  58. 58. Miller, R.L., et al. Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod. Antiviral Res. 1999; 44: p. 31–42.
  59. 59. Hirokawa, D., et al. Treatment of recalcitrant herpes simplex virus with topical imiquimod. Cutis. 2011; 88: p. 276–277.
  60. 60. Kan, Y., et al. Imiquimod suppresses propagation of herpes simplex virus 1 by upregulation of cystatin A via the adenosine receptor A1 pathway. J Virol. 2012; 86: p. 10338–10346. DOI:10.1128/JVI.01196-12.
  61. 61. Lascaux, A.S., et al. Successful treatment of aciclovir and foscarnet resistant herpes simplex virus lesions with topical imiquimod in patients infected with human immunodeficiency virus type 1. J Med Virol. 2012; 84: p. 194–197. DOI:10.1002/jmv.23188.
  62. 62. Deza, G., et al. Successful treatment of hypertrophic herpes simplex genitalis in HIV-infected patient with topical imiquimod. J Dermatol. 2015; 42: p. 1176–1178. DOI:10.1111/1346-8138.12969.
  63. 63. Alexopoulou, L., et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413: p. 732–738. DOI: 10.1038/35099560.
  64. 64. Reinert, L.S., et al. TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. J Clin Invest. 2012; 122: p. 1368–1376. DOI:10.1172/JCI60893.
  65. 65. Liu, Z., et al. HSV-1 activates NF-kappaB in mouse astrocytes and increases TNF-alpha and IL-6 expression via Toll-like receptor 3. Neurol Res. 2013; 35: p. 755–762. DOI:10.1179/016164113X13703372991516.
  66. 66. Casrouge, A., et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science. 2006; 314: p. 308–312. DOI:10.1126/science.1128346.
  67. 67. Zhang, S.Y., et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007; 317: p. 1522–1527. DOI:10.1126/science.1139522.
  68. 68. Guo, Y., et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011; 208: p. 2083–2098. DOI:10.1084/jem.20101568.
  69. 69. Mork, N., et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015; 16: p. 552–566. DOI:10.1038/gene.2015.46.
  70. 70. Lafaille, F.G., et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature. 2012; 491: p. 769–773. DOI:10.1038/nature11583.
  71. 71. Lim, H.K., et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014; 83: p. 1888–1897. DOI:10.1212/WNL.0000000000000999.
  72. 72. Andersen, L.L., et al. Functional IRF3 deficiency in a patient with herpes simplex encephalitis. J Exp Med. 2015; 212: p. 1371–1379. DOI:10.1084/jem.20142274.
  73. 73. Ashkar, A.A., et al. Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA. J Infect Dis.. 2004; 190: p. 1841–1849. DOI:10.1086/425079.
  74. 74. Gianni, T. and G. Campadelli-Fiume. AlphaVbeta3-integrin relocalizes nectin1 and routes herpes simplex virus to lipid rafts. J Virol. 2012; 86: p. 2850–2855. DOI:10.1128/JVI.06689-11.
  75. 75. Gianni, T., V. Leoni, and G. Campadelli-Fiume. Type I interferon and NF-kappaB activation elicited by herpes simplex virus gH/gL via alphavbeta3 integrin in epithelial and neuronal cell lines. J Virol. 2013; 87: p. 13911–1396. DOI: 10.1128/JVI.01894-13.
  76. 76. Gianni, T., et al. Alphavbeta3-integrin is a major sensor and activator of innate immunity to herpes simplex virus-1. Proc Natl Acad Sci U S A. 2012; 109: p. 19792–19797. DOI:10.1073/pnas.1212597109.
  77. 77. Ariza, M.E., R. Glaser, and M.V. Williams. Human herpesviruses-encoded dUTPases: a family of proteins that modulate dendritic cell function and innate immunity. Front Microbiol. 2014; 5: p. 504. DOI:10.3389/fmicb.2014.00504.
  78. 78. Sato, A., M.M. Linehan, and A. Iwasaki. Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci U S A. 2006; 103: p. 17343–17348. DOI:10.1073/pnas.0605102103.
  79. 79. Kurt-Jones, E.A., et al. Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci U S A. 2004; 101: p. 1315–1320. DOI:10.1073/pnas.0308057100.
  80. 80. Schachtele, S.J., et al. Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2. J Neuroinflammation. 2010; 7: p. 35. DOI:10.1186/1742-2094-7-35.
  81. 81. Shu, M., et al. Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the UL47 tegument protein. Proc Natl Acad Sci U S A. 2013; 110: p. E1669–E1675. DOI:10.1073/pnas.1305475110.
  82. 82. Taddeo, B., W. Zhang, and B. Roizman. The herpes simplex virus host shutoff RNase degrades cellular and viral mRNAs made before infection but not viral mRNA made after infection. J Virol. 2013; 87: p. 4516–4522. DOI:10.1128/JVI.00005-13.
  83. 83. Finnen, R.L., et al. The herpes simplex virus 2 virion-associated ribonuclease vhs interferes with stress granule formation. J Virol. 2014; 88: p. 12727–12739. DOI: 10.1128/JVI.01554-14.
  84. 84. Schoggins, J.W. Interferon-stimulated genes: roles in viral pathogenesis. Curr Opin Virol. 2014; 6: p. 40–46. DOI:10.1016/j.coviro.2014.03.006.
  85. 85. Theofilopoulos, A.N., et al. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005; 23: p. 307–336. DOI:10.1146/annurev.immunol.23.021704.115843.
  86. 86. Al-khatib, K., et al. Distinctive roles for 2′,5′-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-beta. J Immunol. 2004; 172: p. 5638–5647.
  87. 87. Diebold, S.S., et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004; 303: p. 1529–1531. DOI: 10.1126/science.1093616.
  88. 88. Hemmi, H., et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002; 3: p. 196–200. DOI:10.1038/ni758.
  89. 89. Donnelly, R.P. and S.V. Kotenko. Interferon-lambda: a new addition to an old family. J Interferon Cytokine Res. 2010; 30: p. 555–564. DOI:10.1089/jir.2010.0078.
  90. 90. Peng, T., et al. Evasion of the mucosal innate immune system by herpes simplex virus type 2. J Virol. 2009; 83: p. 12559–12568. DOI:10.1128/JVI.00939-09.
  91. 91. Lin, R., et al. The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes. J Virol. 2004; 78: p. 1675–1684.
  92. 92. Wang, S., et al. Herpes simplex virus 1 serine/threonine kinase US3 hyperphosphorylates IRF3 and inhibits beta interferon production. J Virol. 2013; 87: p. 12814–12827. DOI:10.1128/JVI.02355-13.
  93. 93. Xing, J., et al. Herpes simplex virus 1-encoded tegument protein VP16 abrogates the production of beta interferon (IFN) by inhibiting NF-kappaB activation and blocking IFN regulatory factor 3 to recruit its coactivator CBP. J Virol. 2013; 87: p. 9788–9801. DOI:10.1128/JVI.01440-13.
  94. 94. Wang, S., et al. Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3. J Virol. 2013; 87: p. 11851–11860. DOI:10.1128/JVI.01211-13.
  95. 95. Milligan, G.N. and D.I. Bernstein. Interferon-gamma enhances resolution of herpes simplex virus type 2 infection of the murine genital tract. Virology. 1997; 229: p. 259–268. DOI:10.1006/viro.1997.8441.
  96. 96. Johnson, K.E., B. Song, and D.M. Knipe. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling. Virology. 2008; 374: p. 487–494. DOI:10.1016/j.virol.2008.01.001.
  97. 97. Chee, A.V. and B. Roizman. Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites. J Virol. 2004; 78: p. 4185–4196.
  98. 98. Johnson, K.E. and D.M. Knipe. Herpes simplex virus-1 infection causes the secretion of a type I interferon-antagonizing protein and inhibits signaling at or before Jak-1 activation. Virology. 2010; 396: p. 21–29. DOI:10.1016/j.virol.2009.09.021.
  99. 99. Fung, K.Y., et al. Interferon-epsilon protects the female reproductive tract from viral and bacterial infection. Science. 2013; 339: p. 1088–1092. DOI: 10.1126/science.1233321.
  100. 100. Hermant, P., et al. IFN-epsilon is constitutively expressed by cells of the reproductive tract and is inefficiently secreted by fibroblasts and cell lines. PLoS One. 2013; 8: p. e71320. DOI:10.1371/journal.pone.0071320.
  101. 101. Mangan, N., et al. A role for interferon epsilon in the innate immune response in the female reproductive tract. Cytokine. 2014; 70: p. 58.
  102. 102. Shupack, J., et al. Topical alpha-interferon ointment with dimethyl sulfoxide in the treatment of recurrent genital herpes simplex. Dermatology. 1992; 184: p. 40–44.
  103. 103. Luker, G.D., et al. Bioluminescence imaging reveals systemic dissemination of herpes simplex virus type 1 in the absence of interferon receptors. J Virol. 2003; 77: p. 11082–11093. DOI: 10.1128/JVI.77.20.11082-11093.2003
  104. 104. Zhang, S.Q., et al. Interleukin 29 enhances expression of Toll receptor 3 and mediates antiviral signals in human keratinocytes. Inflamm Res. 2011; 60: p. 1031–1037. DOI:10.1007/s00011-011-0364-z.
  105. 105. Zhou, L., et al. IL-29/IL-28A suppress HSV-1 infection of human NT2-N neurons. J Neurovirol. 2011; 17: p. 212–219. DOI:10.1007/s13365-011-0031-8.
  106. 106. Iversen, M.B., et al. Expression of type III interferon (IFN) in the vaginal mucosa is mediated primarily by dendritic cells and displays stronger dependence on NF-kappaB than type I IFNs. J Virol. 2010; 84: p. 4579–4586. DOI: 10.1128/JVI.02591-09.
  107. 107. Green, D.R. and F. Llambi. Cell death signaling. Cold Spring Harb Perspect Biol. 2015; 7:a006080. DOI:10.1101/cshperspect.a006080.
  108. 108. Aubert, M., E.M. Krantz, and K.R. Jerome. Herpes simplex virus genes Us3, Us5, and Us12 differentially regulate cytotoxic T lymphocyte-induced cytotoxicity. Viral Immunol. 2006; 19: p. 391–408. DOI:10.1089/vim.2006.19.391.
  109. 109. Wang, X., C. Patenode, and B. Roizman. US3 protein kinase of HSV-1 cycles between the cytoplasm and nucleus and interacts with programmed cell death protein 4 (PDCD4) to block apoptosis. Proc Natl Acad Sci U S A. 2011; 108: p. 14632–14636. DOI:10.1073/pnas.1111942108.
  110. 110. Yamauchi, Y., et al. Herpes simplex virus UL14 protein blocks apoptosis. Microbiol Immunol. 2003; 47: p. 685–689. DOI: 10.1111/j.1348-0421.2003.tb03432.x
  111. 111. Golembewski, E.K., et al. The HSV-2 protein ICP10PK prevents neuronal apoptosis and loss of function in an in vivo model of neurodegeneration associated with glutamate excitotoxicity. Exp Neurol. 2007; 203: p. 381–393. DOI:10.1016/j.expneurol.2006.08.022.
  112. 112. Sieg, S., et al. Herpes simplex virus type 2 inhibition of Fas ligand expression. J Virol. 1996; 70: p. 8747–8751.
  113. 113. Morton, E.R. and J.A. Blaho. Herpes simplex virus blocks Fas-mediated apoptosis independent of viral activation of NF-kappaB in human epithelial HEp-2 cells. J Interferon Cytokine Res. 2007; 27: p. 365–376. DOI:10.1089/jir.2006.0143.
  114. 114. Rogge, M., et al. Therapeutic use of soluble Fas ligand ameliorates acute and recurrent herpetic stromal keratitis in mice. Invest Ophthalmol Vis Sci. 2015; 56: p. 6377–6386. DOI:10.1167/iovs.15-16588.
  115. 115. Jerome, K.R., et al. HSV and glycoprotein J inhibit caspase activation and apoptosis induced by granzyme B or Fas. J Immunol. 2001; 167: p. 3928–3935.
  116. 116. Zhou, G., et al. Glycoprotein D or J delivered in trans blocks apoptosis in SK-N-SH cells induced by a herpes simplex virus 1 mutant lacking intact genes expressing both glycoproteins. J Virol. 2000; 74: p. 11782–11791. DOI:10.1128/JVI.74.24.11782-11791.2000.
  117. 117. Guo, H., et al. Herpes simplex virus suppresses necroptosis in human cells. Cell Host Microbe. 2015; 17: p. 243–251. DOI:10.1016/j.chom.2015.01.003.
  118. 118. Bosnjak, L., et al. Herpes simplex virus infection of human dendritic cells induces apoptosis and allows cross-presentation via uninfected dendritic cells. J Immunol. 2005; 174: p. 2220–2227. DOI:10.4049/jimmunol.174.4.2220.
  119. 119. Stefanidou, M., et al. Herpes simplex virus 2 (HSV-2) prevents dendritic cell maturation, induces apoptosis, and triggers release of proinflammatory cytokines: potential links to HSV-HIV synergy. J Virol. 2013; 87: p. 1443–1453. DOI:10.1128/JVI.01302-12.
  120. 120. Kather, A., et al. Herpes simplex virus type 1 (HSV-1)-induced apoptosis in human dendritic cells as a result of downregulation of cellular FLICE-inhibitory protein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequences. J Virol. 2010; 84: p. 1034–1046. DOI:10.1128/JVI.01409-09.
  121. 121. Iannello, A., et al. Herpes simplex virus type 1-induced FasL expression in human monocytic cells and its implications for cell death, viral replication, and immune evasion. Viral Immunol. 2011; 24: p. 11–26. DOI:10.1089/vim.2010.0083.
  122. 122. Huang, Z., et al. RIP1/RIP3 binding to HSV-1 ICP6 initiates necroptosis to restrict virus propagation in mice. Cell Host Microbe. 2015; 17: p. 229–242. DOI:10.1016/j.chom.2015.01.002.
  123. 123. Wang, X., et al. Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense. Proc Natl Acad Sci U S A. 2014; 111: p. 15438–15443. DOI: 10.1073/pnas.1412767111.
  124. 124. Himmelein, S., et al. Latent herpes simplex virus 1 infection does not induce apoptosis in human trigeminal Ganglia. J Virol. 2015; 89: p. 5747–5750. DOI: 10.1128/JVI.03481-14.
  125. 125. Carpenter, D., et al. The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) protects cells against cold-shock-induced apoptosis by maintaining phosphorylation of protein kinase B (AKT). J Neurovirol. 2015; 21: p. 568–575. DOI: 10.1007/s13365-015-0361-z.
  126. 126. Dev, A., et al. NF-kappaB and innate immunity. Curr Top Microbiol Immunol. 2011; 349: p. 115–143. DOI: 10.1007/82_2010_102.
  127. 127. Wang, K., et al. Herpes simplex virus 1 protein kinase US3 hyperphosphorylates p65/RelA and dampens NF-kappaB activation. J Virol. 2014; 88: p. 7941–7951. DOI: 10.1128/JVI.03394-13.
  128. 128. Zhang, J., et al. Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-alpha-induced NF-kappaB activation by interacting with p65/RelA and p50/NF-kappaB1. Med Microbiol Immunol. 2013; 202: p. 313–325. DOI:10.1007/s00430-013-0295-0.
  129. 129. Zhang, J., et al. Herpes simplex virus 1 E3 ubiquitin ligase ICP0 protein inhibits tumor necrosis factor alpha-induced NF-kappaB activation by interacting with p65/RelA and p50/NF-kappaB1. J Virol. 2013; 87: p. 12935–12948. DOI:10.1128/JVI.01952-13.
  130. 130. Patel, A., et al. Herpes simplex type 1 induction of persistent NF-kappa B nuclear translocation increases the efficiency of virus replication. Virology. 1998; 247: p. 212–222.
  131. 131. Gregory, D., et al. Efficient replication by herpes simplex virus type 1 involves activation of the IkappaB kinase-IkappaB-p65 pathway. J Virol. 2004; 78: p. 13582–13590. DOI: 10.1128/JVI.78.24.13582-13590.2004.
  132. 132. Ferreira, V.H., et al. Proinflammatory cytokines and chemokines—but not interferon-beta—produced in response to HSV-2 in primary human genital epithelial cells are associated with viral replication and the presence of the virion host shutoff protein. Am J Reprod Immunol. 2013; 70: p. 199–212. DOI: 10.1111/aji.12133.
  133. 133. Huang, W., et al. Herpes simplex virus type 2 infection of human epithelial cells induces CXCL9 expression and CD4+ T cell migration via activation of p38-CCAAT/enhancer-binding protein-beta pathway. J Immunol. 2012; 188: p. 6247–6257. DOI:10.4049/jimmunol.1103706.
  134. 134. Thapa, M., et al. CXCL9 and CXCL10 expression are critical for control of genital herpes simplex virus type 2 infection through mobilization of HSV-specific CTL and NK cells to the nervous system. J Immunol. 2008; 180: p. 1098–1106. DOI:10.4049/​jimmunol.180.2.1098
  135. 135. Conrady, C.D., et al. IFN-alpha-driven CCL2 production recruits inflammatory monocytes to infection site in mice. Mucosal Immunol. 2013; 6: p. 45–55. DOI: 10.1038/mi.2012.46.
  136. 136. Stock, A.T., J.M. Smith, and F.R. Carbone. Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection. J Exp Med. 2014; 211: p. 751–759. DOI:10.1084/jem.20132183.
  137. 137. Conrady, C.D., et al. Microglia and a functional type I IFN pathway are required to counter HSV-1-driven brain lateral ventricle enlargement and encephalitis. J Immunol. 2013; 190: p. 2807–2817. DOI:10.4049/jimmunol.1203265.
  138. 138. Chucair-Elliott, A.J., et al. Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia. 2014; 62: p. 1418–1434. DOI: 10.1002/glia.22689.
  139. 139. Aoki, R., et al. Mast cells play a key role in host defense against herpes simplex virus infection through TNF-alpha and IL-6 production. J Invest Dermatol. 2013; 133: p. 2170–2179. DOI: 10.1038/jid.2013.150.
  140. 140. Boivin, N., et al. The combination of valacyclovir with an anti-TNF alpha antibody increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis. Antiviral Res. 2013; 100: p. 649–653. DOI: 10.1016/j.antiviral.2013.10.007.
  141. 141. Masson, L., et al. Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study. Sex Transm Infect. 2014; 90: p. 580–587. DOI:10.1136/sextrans-2014-051601.
  142. 142. Wasserheit, J.N. Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis. 1992; 19: p. 61–77.
  143. 143. Barnabas, R.V., et al. Impact of herpes simplex virus type 2 on HIV-1 acquisition and progression in an HIV vaccine trial (the Step study). J Acquir Immune Defic Syndr. 2011; 57: p. 238–244. DOI: 10.1097/QAI.0b013e31821acb5.
  144. 144. Freeman, E.E., et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. Aids. 2006; 20: p. 73–83.
  145. 145. Corey, L., et al. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr. 2004; 35: p. 435–445.
  146. 146. Nixon, B., et al. Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease. J Infect Dis.. 2014; 209: p. 510–522. DOI:10.1093/infdis/jit472.
  147. 147. Johnson, K.E., et al. Effects of HIV-1 and herpes simplex virus type 2 infection on lymphocyte and dendritic cell density in adult foreskins from Rakai, Uganda. J Infect Dis. 2011; 203: p. 602–609. DOI: 10.1093/infdis/jiq091.
  148. 148. Rebbapragada, A., et al. Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract. Aids. 2007; 21: p. 589–598. DOI:10.1097/QAD.0b013e328012b896.
  149. 149. Goode, D., et al. HSV-2-driven increase in the expression of alpha4beta7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection. PLoS Pathog. 2014; 10: p. e1004567. DOI:10.1371/journal.ppat.1004567.
  150. 150. Marsden, V., et al. Herpes simplex virus type 2-infected dendritic cells produce TNF-alpha, which enhances CCR5 expression and stimulates HIV production from adjacent infected cells. J Immunol. 2015; 194: p. 4438–4445. DOI:10.4049/jimmunol.1401706.
  151. 151. Sartori, E., et al. Herpes simplex virus type 2 infection increases human immunodeficiency virus type 1 entry into human primary macrophages. Virol J. 2011; 8: p. 166. DOI:10.1186/1743-422X-8-166.
  152. 152. Martinelli, E., et al. HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target. PLoS Pathog. 2011; 7: p. e1002109. DOI:10.1371/journal.ppat.1002109.
  153. 153. de Jong, M.A., et al. Herpes simplex virus type 2 enhances HIV-1 susceptibility by affecting Langerhans cell function. J Immunol. 2010; 185: p. 1633–1641. DOI: 10.4049/jimmunol.0904137.
  154. 154. Svensson, A., et al. Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. J Immunol. 2005; 174: p. 6266–6273. DOI: 10.4049/​jimmunol.174.10.6266.
  155. 155. Bird, M.D., et al. Early resolution of herpes simplex virus type 2 infection of the murine genital tract involves stimulation of genital parenchymal cells by gamma interferon. J Virol. 2007; 81: p. 423–426. DOI:10.1128/JVI.01455-06.
  156. 156. Khan, A.A., et al. Phenotypic and functional characterization of herpes simplex virus glycoprotein B epitope-specific effector and memory CD8+ T cells from symptomatic and asymptomatic individuals with ocular herpes. J Virol. 2015; 89: p. 3776–3792. DOI: 10.1128/JVI.03419-14.
  157. 157. Sato, A., et al. Vaginal memory T cells induced by intranasal vaccination are critical for protective T cell recruitment and prevention of genital HSV-2 disease. J Virol. 2014; 88: p. 13699–13708. DOI:10.1128/JVI.02279-14.
  158. 158. Johnson, A.J., et al. Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection. J Reprod Immunol. 2010; 84: p. 8–15. DOI:10.1016/j.jri.2009.09.007.
  159. 159. Tegla, C.A., et al. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res. 2011; 51: p. 45–60. DOI:10.1007/s12026-011-8239-5.
  160. 160. McNearney, T.A., et al. Herpes simplex virus glycoproteins gC-1 and gC-2 bind to the third component of complement and provide protection against complement-mediated neutralization of viral infectivity. J Exp Med. 1987; 166: p. 1525–1535.
  161. 161. Friedman, H.M., et al. Glycoprotein C of herpes simplex virus 1 acts as a receptor for the C3b complement component on infected cells. Nature. 1984; 309: p. 633–635. DOI: 10.1038/309633a0.
  162. 162. Hook, L.M., et al. Herpes simplex virus type 1 and 2 glycoprotein C prevents complement-mediated neutralization induced by natural immunoglobulin M antibody. J Virol. 2006; 80: p. 4038–4046. DOI:10.1128/JVI.80.8.4038-4046.2006.
  163. 163. Lubinski, J.M., et al. Herpes simplex virus type 1 evades the effects of antibody and complement in vivo. J Virol. 2002; 76: p. 9232–9241. DOI: 10.1128/JVI.76.18.9232-9241.2002
  164. 164. Kim, M., et al. Herpes simplex virus antigens directly activate NK cells via TLR2, thus facilitating their presentation to CD4 T lymphocytes. J Immunol. 2012; 188: p. 4158–4170. DOI:10.4049/jimmunol.1103450.
  165. 165. Frank, G.M., et al. Early responding dendritic cells direct the local NK response to control herpes simplex virus 1 infection within the cornea. J Immunol. 2012; 188: p. 1350–1359. DOI:10.4049/jimmunol.1101968.
  166. 166. Rajasagi, N.K., et al. CD4+ T cells are required for the priming of CD8+ T cells following infection with herpes simplex virus type 1. J Virol. 2009; 83: p. 5256–5268. DOI:10.1128/JVI.01997-08.
  167. 167. Vogel, K., et al. Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections. Immunology. 2014; 143: p. 588–600. DOI: 10.1111/imm.12337.
  168. 168. Grauwet, K., et al. Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1-dependent NK cell-mediated lysis of infected cells. Proc Natl Acad Sci U S A. 2014; 111: p. 16118–16123. DOI:10.1073/pnas.1409485111.
  169. 169. Schepis, D., et al. Herpes simplex virus infection downmodulates NKG2D ligand expression. Scandinavian J Immunol. 2009; 69: p. 429–436. DOI:10.1111/j.1365-3083.2009.02241.x.
  170. 170. Tomazin, R., et al. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO J. 1996; 15: p. 3256.
  171. 171. Campbell, T.M., et al. Varicella-Zoster Virus and herpes simplex virus 1 differentially modulate NKG2D ligand expression during productive infection. J Virol. 2015; 89: p. 7932–7943. DOI: 10.1128/JVI.00292-15.
  172. 172. Halford, W.P., J.L. Maender, and B.M. Gebhardt. Re-evaluating the role of natural killer cells in innate resistance to herpes simplex virus type 1. Virol J. 2005; 2: p. 56. DOI:10.1186/1743-422X-2-56.
  173. 173. Nandakumar, S., et al. Natural killer cells as novel helpers in anti-herpes simplex virus immune response. J Virol. 2008; 82: p. 10820–10831. DOI:10.1128/JVI.00365-08.
  174. 174. Godfrey, D.I., et al. Antigen recognition by CD1d-restricted NKT T cell receptors. Seminars Immunol. 2010; 22: p. 61–67. DOI:10.1016/j.smim.2009.10.004.
  175. 175. Rao, P., et al. Herpes simplex virus 1 glycoprotein B and US3 collaborate to inhibit CD1d antigen presentation and NKT cell function. J Virol. 2011; 85: p. 8093–8104. DOI:10.1128/JVI.02689-10.
  176. 176. Yuan, W., A. Dasgupta, and P. Cresswell. Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling. Nat Immunol. 2006; 7: p. 835–842. DOI:10.1038/ni1364.
  177. 177. Xiong, R., et al. Herpes simplex virus 1 US3 phosphorylates cellular KIF3A to downregulate CD1d expression. J Virol. 2015; 89: p. 6646–6655. DOI: 10.1128/JVI.00214-15.
  178. 178. Iversen, M.B., et al. NKT cell activation by local alpha-galactosylceramide administration decreases susceptibility to HSV-2 infection. Immunobiology. 2015; 220: p. 762–768. DOI:10.1016/j.imbio.2014.12.019.
  179. 179. Raftery, M.J., et al. NKT cells determine titer and subtype profile of virus-specific IgG antibodies during herpes simplex virus Infection. J Immunol. 2014; 192: p. 4294–4302. DOI:10.4049/jimmunol.1300148.
  180. 180. Carreno, L.J., et al. Modulation of the dendritic cell-T-cell synapse to promote pathogen immunity and prevent autoimmunity. Immunotherapy. 2011; 3: p. 6–11. DOI:10.2217/imt.11.38.
  181. 181. Gonzalez, P.A., et al. Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells. Proc Natl Acad Sci U S A. 2008; 105: p. 14999–15004. DOI:10.1073/pnas.0802555105.
  182. 182. Banchereau, J., et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000; 18: p. 767–811. DOI:10.1146/annurev.immunol.18.1.767.
  183. 183. Gonzalez, P.A., et al. Modulation of immunological synapse by membrane-bound and soluble ligands. Cytokine Growth Factor Rev. 2007; 18: p. 19–31. DOI: 10.1016/j.cytogfr.2007.01.003.
  184. 184. Tobar, J.A., P.A. Gonzalez, and A.M. Kalergis. Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fc gamma receptors on dendritic cells. J Immunol. 2004; 173: p. 4058–4065. DOI: 10.4049/​jimmunol.173.6.4058.
  185. 185. Tobar, J.A., et al. Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infect Immun. 2006; 74: p. 6438–6448. DOI:10.1128/IAI.00063-06.
  186. 186. Raftery, M.J., et al. CD1 antigen presentation by human dendritic cells as a target for herpes simplex virus immune evasion. J Immunol. 2006; 177: p. 6207–6214. DOI: 10.4049/​jimmunol.177.9.6207.
  187. 187. Majumder, B., et al. Human immunodeficiency virus type 1 Vpr impairs dendritic cell maturation and T-cell activation: implications for viral immune escape. J Virol. 2005; 79: p. 7990–8003. DOI: 10.1128/JVI.79.13.7990-8003.2005.
  188. 188. Morrow, G., et al. Varicella-zoster virus productively infects mature dendritic cells and alters their immune function. J Virol. 2003; 77: p. 4950–4959. DOI: 10.1128/JVI.77.8.4950-4959.2003
  189. 189. Bueno, S.M., et al. The capacity of Salmonella to survive inside dendritic cells and prevent antigen presentation to T cells is host specific. Immunology. 2008; 124: p. 522–533. DOI:10.1111/j.1365-2567.2008.02805.x.
  190. 190. Jones, C.A., et al. Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J Virol. 2003; 77: p. 11139–11149. DOI: 10.1128/JVI.77.20.11139-11149.2003.
  191. 191. Gobeil, P.A. and D.A. Leib. Herpes simplex virus gamma34.5 interferes with autophagosome maturation and antigen presentation in dendritic cells. mBio. 2012; 3: p. e00267–12. DOI:10.1128/mBio.00267-12.
  192. 192. Yordy, B., et al. A neuron-specific role for autophagy in antiviral defense against herpes simplex virus. Cell Host Microbe. 2012; 12: p. 334–345. DOI: 10.1016/j.chom.2012.07.013.
  193. 193. Elboim, M., et al. HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. PLoS Pathog. 2013; 9: p. e1003226. DOI:10.1371/journal.ppat.1003226.
  194. 194. Wu, B., et al. Herpes simplex virus 1 suppresses the function of lung dendritic cells via caveolin-1. Clin Vaccine Immunol. 2015; 22: p. 883–895. DOI:10.1128/CVI.00170-15.
  195. 195. Kim, M., et al. Relay of herpes simplex virus between Langerhans cells and dermal dendritic cells in human skin. PLoS Pathog. 2015; 11: p. e1004812. DOI:10.1371/journal.ppat.1004812.
  196. 196. Mott, K.R. and H. Ghiasi. Role of dendritic cells in enhancement of herpes simplex virus type 1 latency and reactivation in vaccinated mice. Clin Vaccine Immunol. 2008; 15: p. 1859–1867. DOI:10.1128/CVI.00318-08.
  197. 197. Mott, K.R., et al. A role for the JAK-STAT1 pathway in blocking replication of HSV-1 in dendritic cells and macrophages. Virol J. 2009; 6: p. 56. DOI: 10.1186/1743-422X-6-56.
  198. 198. Kassim, S.H., et al. In vivo ablation of CD11c-positive dendritic cells increases susceptibility to herpes simplex virus type 1 infection and diminishes NK and T-cell responses. J Virol. 2006; 80: p. 3985–3993. DOI:10.1128/JVI.80.8.3985-3993.2006.
  199. 199. Cairns, T.M., et al. Dissection of the antibody response against herpes simplex virus glycoproteins in naturally infected humans. J Virol. 2014; 88: p. 12612–12622. DOI: 10.1128/JVI.01930-14.
  200. 200. Bournazos, S. and J.V. Ravetch. Fc gamma receptor pathways during active and passive immunization. Immunological reviews. 2015; 268: p. 88–103. DOI: 10.1111/imr.12343.
  201. 201. Lubinski, J.M., et al. The herpes simplex virus 1 IgG fc receptor blocks antibody-mediated complement activation and antibody-dependent cellular cytotoxicity in vivo. J Virol. 2011; 85: p. 3239–3249. DOI:10.1128/JVI.02509-10.
  202. 202. Para, M.F., L. Goldstein, and P.G. Spear. Similarities and differences in the Fc-binding glycoprotein (gE) of herpes simplex virus types 1 and 2 and tentative mapping of the viral gene for this glycoprotein. J Virol. 1982; 41: p. 137–144.
  203. 203. Armour, K.L., et al. The contrasting IgG-binding interactions of human and herpes simplex virus Fc receptors. Biochem Soc Trans. 2002; 30: p. 495–500. DOI: 10.1042/bst0300495.
  204. 204. Dilillo, D.J., et al. Broadly neutralizing hemagglutinin stalk-specific antibodies require Fc gamma R interactions for protection against influenza virus in vivo. Nat Med. 2014; 20: p. 143–151. DOI:10.1038/nm.3443.
  205. 205. Hill, A., et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature. 1995; 375: p. 411–415. DOI:10.1038/375411a0.
  206. 206. Imai, T., et al. Us3 kinase encoded by herpes simplex virus 1 mediates downregulation of cell surface major histocompatibility complex class I and evasion of CD8+ T cells. PLoS One. 2013; 8: p. e72050. DOI:10.1371/journal.pone.0072050.
  207. 207. La, S., et al. Herpes simplex virus type 1 glycoprotein D inhibits T-cell proliferation. Mole Cells. 2002; 14: p. 398–403.
  208. 208. Sloan, D.D., et al. Inhibition of TCR signaling by herpes simplex virus. J Immunol. 2006; 176: p. 1825–1833. DOI: 10.4049/​jimmunol.176.3.1825.
  209. 209. Yang, Y., et al. The Us3 protein of herpes simplex virus 1 inhibits T cell signaling by confining linker for activation of T cells (LAT) activation via TRAF6 protein. J Biol Chem. 2015; 290: p. 15670–15678. DOI:10.1074/jbc.M115.646422.
  210. 210. Aubert, M., et al. The virological synapse facilitates herpes simplex virus entry into T cells. J Virol. 2009; 83: p. 6171–6183. DOI:10.1128/JVI.02163-08.
  211. 211. Vanden Oever, M.J. and J.Y. Han. Caspase 9 is essential for herpes simplex virus type 2-induced apoptosis in T cells. J Virol. 2010; 84: p. 3116–3120. DOI: 10.1128/JVI.01726-09.
  212. 212. Veiga-Parga, T., S. Sehrawat, and B.T. Rouse. Role of regulatory T cells during virus infection. Immunol Rev. 2013; 255: p. 182–196. DOI:10.1111/imr.12085.
  213. 213. Fernandez, M.A., et al. T regulatory cells contribute to the attenuated primary CD8+ and CD4+ T cell responses to herpes simplex virus type 2 in neonatal mice. J Immunol. 2008; 180: p. 1556–1564. DOI: 10.4049/​jimmunol.180.3.1556.
  214. 214. Suvas, S., et al. CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med. 2003; 198: p. 889–901. DOI: 10.1084/jem.20030171.
  215. 215. Sloan, D.D. and K.R. Jerome. Herpes simplex virus remodels T-cell receptor signaling, resulting in p38-dependent selective synthesis of interleukin-10. J Virol. 2007; 81: p. 12504–12514. DOI:10.1128/JVI.01111-07.
  216. 216. Sharma, S., et al. Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection. Microbes Infect. 2014; 16: p. 648–660. DOI:10.1016/j.micinf.2014.06.005.
  217. 217. Fernandez, M.A., et al. Treg depletion attenuates the severity of skin disease from ganglionic spread after HSV-2 flank infection. Virology. 2013; 447: p. 9–20. DOI: 10.1016/j.virol.2013.08.027.
  218. 218. Iyer, A.V., et al. Single dose of Glycoprotein K (gK)-deleted HSV-1 live-attenuated virus protects mice against lethal vaginal challenge with HSV-1 and HSV-2 and induces lasting T cell memory immune responses. Virol J. 2013; 10: p. 317. DOI:10.1186/1743-422X-10-317.
  219. 219. Lund, J.M., et al. Coordination of early protective immunity to viral infection by regulatory T cells. Science. 2008; 320: p. 1220–1224. DOI:10.1126/science.1155209.
  220. 220. Mertz, G.J., et al. Double-blind, placebo-controlled trial of a herpes simplex virus type 2 glycoprotein vaccine in persons at high risk for genital herpes infection. J Infect Dis. 1990; 161: p. 653–660. DOI: 10.1093/infdis/161.4.653.
  221. 221. Cheshenko, N., et al. HSV activates Akt to trigger calcium release and promote viral entry: novel candidate target for treatment and suppression. FASEB J. 2013; 27: p. 2584–2599. DOI:10.1096/fj.12-220285.
  222. 222. Kim, M., et al. Immunodominant epitopes in herpes simplex virus type 2 glycoprotein D are recognized by CD4 lymphocytes from both HSV-1 and HSV-2 seropositive subjects. J Immunol. 2008; 181: p. 6604–6615. DOI:10.4049/jimmunol.181.9.6604
  223. 223. Chentoufi, A.A., et al. HLA-A*0201-restricted CD8+ cytotoxic T lymphocyte epitopes identified from herpes simplex virus glycoprotein D. J Immunol. 2008; 180: p. 426–437. DOI: 10.4049/jimmunol.180.1.426.
  224. 224. Nicola, A.V., et al. Structure-function analysis of soluble forms of herpes simplex virus glycoprotein D. J Virol. 1996; 70: p. 3815–3822.
  225. 225. Zhu, X.P., et al. HSV-2 vaccine: current status and insight into factors for developing an efficient vaccine. Viruses. 2014; 6: p. 371–390. DOI:10.3390/v6020371.
  226. 226. Retamal-Díaz, A.R., et al. Immune evasion by herpes simplex viruses. Rev Chilena Infectol. 2015; 32: p. 58–70. DOI:10.4067/S0716-10182015000200013.
  227. 227. Belshe, R.B., et al. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med. 2012; 366: p. 34–43. DOI:10.1056/NEJMoa1103151.
  228. 228. Bernstein, D.I., et al. Safety and immunogenicity of glycoprotein D-adjuvant genital herpes vaccine. Clin Infect Dis. 2005; 40: p. 1271–1281. DOI:10.1086/429240.
  229. 229. Corey, L., et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA. 1999; 282: p. 331–340. DOI:10.1001/jama.282.4.331
  230. 230. Kohl, S., et al. Limited antibody-dependent cellular cytotoxicity antibody response induced by a herpes simplex virus type 2 subunit vaccine. J Infect Dis. 2000; 181: p. 335–339. DOI:10.1086/315208.
  231. 231. Halford, W.P. Antigenic breadth: a missing ingredient in HSV-2 subunit vaccines? Expert Rev Vaccines. 2014; 13: p. 691–710. DOI: 10.1586/14760584.2014.910121.
  232. 232. Chentoufi, A.A., et al. Towards a rational design of an asymptomatic clinical herpes vaccine: the old, the new, and the unknown. Clin Dev Immunol. 2012; 2012: p. 187585. DOI:10.1155/2012/187585.
  233. 233. Petro, C., et al. Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease. Elife. 2015; 4:e06054. DOI:10.7554/eLife.06054
  234. 234. Halford, W.P., et al. A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine. PLoS One. 2011; 6: p. e17748. DOI:10.1371/journal.pone.0017748.
  235. 235. Halford, W.P., et al. Antibodies are required for complete vaccine-induced protection against herpes simplex virus 2. PLoS One. 2015; 10: p. e0145228. 10.1371/journal.pone.0145228 10.1371/journal.pone.0145228.
  236. 236. Geltz, J.J., E. Gershburg, and W.P. Halford. Herpes simplex virus 2 (HSV-2) infected cell proteins are among the most dominant antigens of a live-attenuated HSV-2 vaccine. PLoS One. 2015; 10: p. e0116091. DOI:10.1371/journal.pone.0116091.
  237. 237. Da Costa, X., et al. Construction, phenotypic analysis, and immunogenicity of a UL5/UL29 double deletion mutant of herpes simplex virus 2. J Virol. 2000; 74: p. 7963–7971. DOI:10.1128/JVI.74.17.7963-7971.2000.
  238. 238. Mundle, S.T., et al. High-purity preparation of HSV-2 vaccine candidate ACAM529 is immunogenic and efficacious in vivo. PLoS One. 2013; 8: p. e57224. DOI:10.1371/journal.pone.0057224.
  239. 239. Diaz, F.M. and D.M. Knipe. Protection from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus. Virology. 2016; 488: p. 61–67. DOI: 10.1016/j.virol.2015.10.033.
  240. 240. Wang, K., et al. A Herpes simplex virus 2 (HSV-2) gD mutant impaired for neural tropism is superior to an HSV-2 gD subunit vaccine to protect animals from challenge with HSV-2. J Virol. 2015; 90: p. 562–574. DOI:10.1128/JVI.01845-15.
  241. 241. Casanova, G., et al. A double-blind study of the efficacy and safety of the ICP10PK vaccine against recurrent genital HSV-2 infections. Cutis. 2002; 70: p. 235–239. DOI:n/d.
  242. 242. Awasthi, S., et al. Live attenuated herpes simplex virus 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread. J Virol. 2012; 86: p. 4586–4598. DOI:10.1128/JVI.07203-11.
  243. 243. de Bruyn, G., et al. A randomized controlled trial of a replication defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes among immunocompetent subjects. Vaccine. 2006; 24: p. 914–920. DOI: 10.1016/j.vaccine.2005.08.088.
  244. 244. Boukhvalova, M., et al. Efficacy of the herpes simplex virus 2 (HSV-2) glycoprotein D/AS04 vaccine against genital HSV-2 and HSV-1 infection and disease in the cotton rat sigmodon hispidus model. J Virol. 2015; 89: p. 9825–9840. DOI:10.1128/JVI.01387-15.
  245. 245. Srivastava, R., et al. HLA-A02:01-restricted epitopes identified from the herpes simplex virus tegument protein VP11/12 preferentially recall polyfunctional effector memory CD8+ T cells from seropositive asymptomatic individuals and protect humanized HLA-A*02:01 transgenic mice against ocular herpes. J Immunol. 2015; 194: p. 2232–2248. DOI:10.4049/jimmunol.1402606.
  246. 246. Khan, A.A., et al. Therapeutic immunization with a mixture of herpes simplex virus 1 glycoprotein D-derived "asymptomatic" human CD8+ T-cell epitopes decreases spontaneous ocular shedding in latently infected HLA transgenic rabbits: association with low frequency of local PD-1+ TIM-3+ CD8+ exhausted T cells. J Virol. 2015; 89: p. 6619–6632. DOI:10.1128/JVI.00788-15.
  247. 247. Srivastava, R., et al. A herpes simplex virus type 1 human asymptomatic CD8+ T-cell epitopes-based vaccine protects against ocular herpes in a "humanized" HLA transgenic rabbit model. Invest Ophthalmol Vis Sci. 2015; 56: p. 4013–4028. DOI: 10.1167/iovs.15-17074.
  248. 248. Cattamanchi, A., et al. Phase I study of a herpes simplex virus type 2 (HSV-2) DNA vaccine administered to healthy, HSV-2-seronegative adults by a needle-free injection system. Clin Vaccine Immunol. 2008; 15: p. 1638–1643. DOI:10.1128/CVI.00167-08.
  249. 249. Dutton, J.L., et al. A novel DNA vaccine technology conveying protection against a lethal herpes simplex viral challenge in mice. PLoS One. 2013; 8: p. e76407. DOI: 10.1371/journal.pone.0076407.
  250. 250. Kolb, A.W., C. Ane, and C.R. Brandt. Using HSV-1 genome phylogenetics to track past human migrations. PLoS One. 2013; 8: p. e76267. DOI:10.1371/journal.pone.0076267.

Written By

Angello R. Retamal-Díaz, Eduardo Tognarelli, Alexis M. Kalergis, Susan M. Bueno and Pablo A. González

Submitted: November 19th, 2015 Reviewed: May 6th, 2016 Published: September 7th, 2016