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Inhibition of HIV Replication by Host Cellular Factors

Written By

J.M. Azevedo-Pereira, Pedro Canhão, Marta Calado, Quirina Santos- Costa and Pedro Barroca

Submitted: 06 June 2014 Published: 02 September 2015

DOI: 10.5772/60795

From the Edited Volume

Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

Edited by Ibeh Bartholomew Okechukwu

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1. Introduction

Human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) infection leads to immunological failure and Acquired Immunodeficiency Syndrome (AIDS). During transmission and dissemination within a new host, HIV must overcome several cellular mechanisms aiming to inhibit or restrict its infection and its spread to other host cells. Not surprisingly, as a well-adapted human pathogen, HIV has evolved in order to counteract and subvert these cellular inhibitory factors. Defining how viral and cellular proteins interact remains a critical area of research with direct implications in the knowledge of transmission, pathogenic mechanisms, vaccine design and molecular targets for therapeutic intervention.

In this chapter, the mechanisms involved in the inhibitory activity of some cellular proteins and the way HIV evades those host cell restrictions will be focused on. Particular attention will be given to the tripartite motif 5 (TRIM5) protein family, involved in viral uncoating; the retroviral protection factors, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) and Tetherin, involved in the reverse transcription and viral release respectively; and to the sterile alpha motif [SAM] and histidine/aspartic acid [HD] domain-containing protein 1 (SAMHD1), which mediates the restriction of HIV-1 replication in dendritic cells. This review will also delve into the mechanisms of two recently described factors: MxB, which restricts HIV nuclear import and integration, and cholesterol-25-hydroxylase that converts cholesterol to a soluble antiviral factor (25-hydroxycholesterol) that blocks HIV fusion with target cells.


2. Brief overview on HIV replication cycle

The replication cycle of HIV can be divided into five major steps: (i) virus-receptor interactions and fusion; (ii) reverse transcription and proviral integration; (iii) HIV genomic DNA transcription; (iv) HIV mRNA splicing, nuclear export and translation; and (v) viral assembly, release and maturation (Figure 1).

The first step of the cycle begins with the binding of the virion gp120 surface subunit (SU glycoprotein) to CD4 receptor present in T-cells, macrophages and dendritic cells. The SU glycoprotein and the gp41 transmembrane subunit (TM glycoprotein) remain associated by non-covalent binding. Both SU and TM are proteolytically cleaved from the envelope (Env) precursor protein by a cellular convertase, furin, within the endoplasmatic reticulum (ER). The SU glycoprotein allows viral binding to cellular receptors – CD4 and a coreceptor belonging to the chemokine receptor’s family – while the TM protein is involved in the fusion between the viral envelope and the host cell membrane [1]. After initial binding to CD4, SU undergoes structural changes that lead to the exposure (or formation) of the coreceptor-binding site. Although several chemokine receptors were identified as mediators of HIV entry in vitro, CCR5 and CXCR4 seem to be the two major coreceptors [2, 3]. After SU glycoprotein binding to co-receptor additional conformational changes are observed, exposing the N-terminal region of TM (dubbed the “fusion peptide”), which mediates the fusion between the viral and host membranes (reviewed in [4, 5]). This viral fusion process may occur through a direct pH-independent fusion mechanism with plasma membrane [6], or via endocytosis and fusion with endosomes [7].

After viral fusion, the viral capsid enters the cytoplasm and the viral RNA is converted to double-stranded DNA, a reaction mediated by the viral reverse transcriptase (RT), that occurs in a cytoplasmic complex named the reverse transcriptase complex (RTC). RT has three essential activities for virus replication: RNA-dependent DNA polymerase (i.e. reverse transcriptase), RNase H activity that cleaves the genomic RNA in RNA/ DNA hybrids during cDNA synthesis, and DNA-dependent DNA polymerase activity (for synthesis of the second strand of the proviral DNA). The result is a double-stranded DNA replica of the original genomic RNA. The double-stranded viral DNA, as part of the preintegration complex (PIC), penetrates the host cell nucleus through the pores in the nuclear membrane. Another viral enzyme, integrase, inserts the double-stranded viral DNA in the host cell chromosomal DNA (reviewed in [8]). The PIC is composed of several cellular and viral components, e.g. viral DNA, RT, integrase (IN), capsid (CA), matrix (MA) and Vpr proteins. In activated cells, the proviral DNA is transcribed, acting as a template for mRNA synthesis. The viral mRNA exists as three distinct classes: multiply spliced (~2kb), single-spliced (4-5kb) and unspliced (9kb). The multiply spliced transcripts are the first to accumulate soon after infection and encode the regulatory proteins Tat, Rev and Nef. The accumulation of Rev protein enables the efficient nuclear export of single-spliced and unspliced mRNA and to an increase in the levels of these mRNAs (reviewed in [9]).

Figure 1.

Schematic representation of HIV replication cycle. HIV initiates infection by attaching (1) to cellular receptors: CD4 and a chemokine receptor (co-receptor). The interactions with both receptors trigger the fusion between viral envelope with cellular membrane, either after endocytosis (2A) or by direct fusion with plasma membrane (2B). The release of viral nucleocapside into the cytoplasm (3) precedes the formation of the reverse transcriptase complex (RTC) where the reverse transcription takes place (4). The RTC transforms to the preintegration complex (PIC), composed by several cellular and viral components, that is imported to the nucleus where viral DNA is integrated into cellular chromosomal DNA (5 and 6). The proviral DNA is then transcribed (7) and mRNA migrates to the cytoplasm and translated to viral proteins (8). Assembly of different components of viral particles occurs at plasma membrane (9). After egress and release of immature virions (10), the proteolytical cleavage of Gag polyprotein takes place leading to mature virions (11).

After replication, transcription and translation, the viral genome information is ready to proceed to the final step: the viral assembly, the release and maturation of recently formed virions. The nucleocapsid assembly occurs through protein-protein interactions mediated by the uncleaved Gag polyprotein – through the capsid (CA) domain [10] – that also recruits the viral genomic RNA, through the interaction between the nucleocapsid (NC) domain and the RNA packaging signal (Psi sequence) [11]. The NC domain also mediates the formation of the RNA dimer via a palindromic sequence in the dimer linkage structure (DLS) sequence, which is located in the Psi sequence. In addition, specific cellular tRNAs are packaged. The assembly of the virus particle, which final steps occur at the plasma membrane (reviewed in [12]), is partly regulated by the Vpu and Vif proteins, which play an important role in the assembly of the virus. At the cell membrane, the immature viruses are released and maturation takes place through polypeptide cleavage mediated by the viral protease. The mature virus is now able to infect other cells.


3. Organization of viral genome

The majority of replication competent retroviruses depend on three genes: "group specific-antigen" (gag), "polymerase" (pol) and "envelope"(env) genes. The “classic” structure of a retroviral genome is: 5'LTR-gag-pol-env-LTR 3 ' (Figure 2). The non-coding LTR ('long terminal repeat") represents the two ends of the viral genome and they are linked to host cell DNA after integration. The gag and env genes encode the core and the viral envelope glycoproteins respectively. The pol gene encodes for the RT, IN and protease [13]. In addition, HIV contains in its 9.749 kb RNA, six additional genes: vif, vpu (only in HIV-1), vpr, vpx (only in HIV-2), tat, rev, and nef) which contribute to their genetic complexity and helps virus in several steps during replication cycle [14].

Figure 2.

HIV-1 genome organization. The major viral proteins encoded by gag, pol and env genes are indicated in red. Numbers indicate the beginning and ending of each gene according to nucleotide numbering of HXB2CG HIV-1 strain (GenBank accession number: K03455).

The vif gene codes for Vif, a protein that increases the infectivity of the HIV particle. This protein is found inside HIV-infected cells, and its main function is to interfere with one of the innate immune system's defenses - a cellular protein called APOBEC3G [15].

The "Viral protein U", (coded by vpu gene), enhances the release of new viral particles, helping them to bud from the host cell. Vpu also works within the infected cell to enhance the degradation of CD4 protein. This has the effect of reducing the amount of CD4 present in plasma membrane, therefore reducing the likelihood of superinfection [16].

The "Viral protein R", (coded by vpr gene), is incorporated into viral particles through a specific interaction with Gag proteins. It has several functions during intracellular steps of viral replication. For instance, Vpr is present in the PIC and has been shown to influence the reverse transcription and the nuclear import of viral DNA; it also modulates cell cycle progression and apoptosis of infected cell [17].

Tat and Rev are regulatory proteins coded by tat and rev genes. They are present in the nucleus of infected cells and bind to defined regions of the viral DNA and RNA. These proteins enhances the transcription of proviral DNA into mRNA, promote the RNA elongation, stimulate the transport of HIV-1 mRNA from the nucleus to the cytoplasm and also are essential for translation [9].

Tat is a regulatory transactivator protein, which enhances the activation of HIV long terminal repeat (LTR) increasing the efficiency of HIV genomic transcription. This enhancement is also the result of additional interaction between Tat and cellular transcription factors such as NF-κB and SP-1. Furthermore, Tat also plays a crucial role in AIDS pathogenesis, especially in the development of HIV-associated dementia, dysregulation of cytokine expression and induction of apoptosis [9]. As referred earlier in this chapter, Rev facilitates the nuclear export of single-spliced and unspliced viral mRNAs (~4 kb and ~9 kb mRNAs respectively). The molecular mechanism underlying Rev activity involves a direct interaction between Rev protein and a cis-acting sequence-specific target named RRE (Rev-responsive element). RRE is found within the env gene in all incompletely spliced mRNAs [9, 18]. It has been shown that Nef protein has several functions. It induces down-regulation of CD4 [19] and the HLA class I and II molecules from the surface of HIV infected cells [20], which may represent an important escape mechanism for the virus to avoid recognition by CD4+ T cells. Nef may also interfere with T cell activation, as a result of selective binding to various proteins that are involved in intracellular signaling [21].


4. Cellular factors with inhibitory activity on HIV replication and implications in viral pathogenesis

Innate immunity had evolved as a mechanism to defend eukaryotes from bacterial and viral infections. These mechanisms rely on different cellular restriction factors that suppress the replication of the pathogens, namely retroviruses [22].

During HIV-1 infection, incoming viral RNA triggers a TLR7/8-mediated innate immune response, resulting in the production of type I interferon (IFN). In particular IFNα has been shown to be up-regulated after TLR sensing during acute infection with HIV-1 or SIV [23-25]. Accordingly, initial observations in vitro revealed that pre-treatment of macrophages with type-I IFN inhibited the replication of HIV-1, indicating that potent inhibitory factors were induced after IFN exposure [26, 27]. Most of them are still uncharacterized.

The identification of cellular restriction factors and the viral proteins that antagonize those restrictions have stimulated an active area of research that explores crucial mechanisms underlying HIV interference with cellular restriction factors and innate immunity. In this subchapter specific cellular factors with inhibitory activity on HIV replication are discussed including how viral-encoded proteins counteract these factors.

4.1. TRIM5α

The search for the mechanisms underlying the innate cellular resistance to retroviral infections shown by different non-human primate species, has led to the identification of a cytoplasmic factor that prevented infection of Old World monkeys by HIV-1 [28]. This factor – TRIM5α – was identified as a member of the tripartite motif (TRIM) family of proteins, a large family of cellular proteins with distinct biological activities including innate immune signaling [29]. After its initial identification in rhesus macaques (rhTRIM5α) [28] and owl monkeys (TRIMCyp) [30], TRIM5α was also identified as a retroviral restriction factor in humans [31, 32] that is induced by both type I and type II IFN [33].

Different models have been proposed for retroviral inhibition mediated by TRIM5 proteins [34]. They suggest that these proteins mediate restriction by directly binding to specific determinants in the viral CA protein, blocking HIV replication soon after viral release in host cell cytoplasm. The TRIM proteins family is defined by three domains (RING, B-Box2, and Coiled- Coil), which are present in all members of this family. The N-terminal RING domain possesses E3 ubiquitin ligase activity that is crucial for retrovirus restriction [35, 36]. The B-Box2 and Coiled Coil (CC) domains are thought to contribute to the higher and low order multimerization of TRIM5α, respectively. The TRIM5α also possesses a C-terminal capsid binding domain that mediates specific recognition and restriction of certain retroviruses [37]. The recognition of viral capsid determinants (CA protein) relies on three variable regions present in the C-terminal domain of TRIM5α, and apparently they are equally involved in retrovirus recognition and restriction [38-41].

Several studies have addressed the mechanisms by which TRIM5α protein prevents viral infection and different models have been proposed to explain this restriction. The “accelerated uncoating” model was based on the observation that cytosolic CA protein was specifically dissociated in rhTRIM5α-expressing cells [42] leading to the proposal of a “proteasome independent capsid degradation” mechanism. This model suggests that the stripping of capsid protein prevents viral RTC to proceed to subsequent steps in infectious replication cycle, namely the reverse transcription and nuclear import [42]. An alternative model was primarily based on the observation that proteasome inhibitors allows reverse transcription and integration, without affecting the TRIM5α-mediated restriction [43, 44]. Accordingly, a “two-step restriction mechanism” was proposed, suggesting that restriction activity of TRIM5α occurs by both proteasome-dependent and -independent pathways. The relative contribution of each pathway is apparently dependent on host cells-viruses combinations [45].

4.2. APOBEC3

One important form of intrinsic immunity against retroviral infections is provided by apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family proteins, and particularly by human APOBEC3G (A3G) and APOBEC3F (A3F) [46-49]. These two proteins are cellular antiretroviral factors that possess inhibitory activity against HIV-1 replication [22, 48, 50].

APOBEC proteins act on single-stranded DNA or RNA substrates and their main function is to induce alterations in the nucleotide sequence through cytidine deamination, converting cytidines to uridines (C to U) or deoxycytidines (dC) to deoxyuridines (dU).

The A3G protein, which expression seems to be regulated at a transcriptional level through NFAT and IRF binding to specific sites located in A3G promoter region [51, 52], is packed inside newly formed HIV-1 virions by a specific interaction with the amino-terminal region of NC domain of HIV-1 Gag polyprotein [53-57]. As expected due to the interaction with NC, A3G is present in viral core as a ribonucleoprotein complex together with genomic RNA, NC, IN and Vpr [58]. Interestingly, binding of A3G to HIV genomic RNA led to inactivation of deaminase activity, while the action of HIV RNase H, which degrades the RNA chain during reverse transcription activates its enzymatic activity [58]. After viral entry into a new cell and during reverse transcription, the released A3G targets the minus-strand DNA product and induces a dC to dU deamination resulting in a dG to dA hypermutation in the HIV-1 double-stranded DNA genome of the replicating virus. This hypermutation activity ultimately introduces mutations and stop codons that disrupt the normal expression and function of viral proteins [46, 59]. A3G can also interfere directly with viral reverse transcriptase preventing RT-dependent cDNA elongation independently of deaminase activity [60]. Finally there is also evidence suggesting that A3G reduces the integration of HIV-1 DNA by interfering with PIC functions [61, 62]. In addition to A3G, also A3F seems to exhibit inhibitory activity against HIV-1 replication [47, 49, 63, 64].

Despite their ability to hinder HIV replication, these proteins only show their potent inhibitory effect with HIV-1 mutants lacking a functional vif gene, since the Vif protein expressed by wild-type HIV-1 blocks the function of these host cell proteins [50, 65-70]. Basically, Vif binds to A3G in the cytoplasm of infected cell and directs it for polyubiquitination and proteasomal degradation, preventing its inclusion into the newly formed virions thus overcoming the inhibition of viral replication mediated by A3G [67-69, 71]. A cellular E3 ubiquitin ligase complex consisting of cullin5, elonginB, elonginC and RING finger proteins that binds an E2 ubiquitin-conjugated enzyme, induces the polyubiquitination of A3G. This complex is recruited by Vif that connects it to its substrate inducing the polyubiquitination of A3G [67-69, 71-73]. Additionally, Vif also interferes with the translation of A3G mRNA, reducing its intracellular pool [72, 74].

Besides A3G and A3F proteins, the human genome also contains genes encoding five others members of the APOBEC3 family. However, of these five additional genes, apparently only three (APOBEC3A, APOBEC3B and APOBEC3C) are expressed in human cells. Recent data shows that APOBEC3A is recruited at post-entry HIV-1 replication complexes [75-79]. Its expression is induced in monocyte-derived macrophages (MDM) by interferon-alpha (IFN-α) and it seems to promote resistance to HIV-1 infection in MDM [75]. The APOBEC3C protein is a weak inhibitor of wild-type or vif-deficient HIV-1 [63, 64, 80] although it was described, together with APOBEC3B, as a potent inhibitor of simian immunodeficiency virus (SIV) replication [81]. As for A3G, the APOBEC3B protein is also packed inside HIV-1 virions due to a specific interaction with the NC protein. It induces a potent inhibition of HIV-1 replication and it seems to be resistant to HIV-1 Vif protein [82]. However, APOBEC3B is expressed at very low levels in human tissues, in contrast to A3G and A3F [82].

4.3. Tetherin/ BST-2

In early 2008, an additional restriction factor dubbed Tetherin, previously referred to as BST-2, CD317 or HM1.24, was described [83, 84]. The main function of this IFN-induced protein [85, 86] remained elusive until it was identified as an intrinsic antiviral factor that restricts the egress of HIV and other enveloped viruses by tethering mature virions to the host cell membrane [83, 84, 87-91]. Tetherin is a type II membrane protein highly expressed at the plasma membrane of B cells at all differentiation stages, bone-marrow CD34+ cells and T-cells [92]. It has an unusual topology consisting of an amino-terminal cytoplasmic tail (CT), followed by a transmembrane region that anchors tetherin to the plasma membrane and a coiled-coil extracellular domain that is also linked to the plasma membrane by a carboxy-terminal glycophosphatidylinositol (GPI) anchor [93, 94]. Due to the presence of this GPI anchor, tetherin is mainly located in cholesterol-rich microdomains also referred as “lipid rafts”. Tetherin is involved (through the CT domain) in the organization of subapical actin cytoskeleton in polarized epithelial cells [95] and unlike other GPI-anchored proteins, is endocytosed from lipid rafts in a clathrin-mediated pathway [96].

Coincident with the identification of tetherin as an antiviral factor, it was also found that it was the target of the HIV-1 accessory protein Vpu, providing a plausible mechanism for the well-established but ill-defined, virus-release function of Vpu [83]. The Vpu is a small transmembrane (TM) protein encoded by the vpu gene present in the genomes of HIV-1 and some SIV strains, but absent in HIV-2. It is anchored to the plasma membrane of the infected cell by its amino-terminal region. Initial studies showed that Vpu protein besides its ability to degrade CD4 protein [97], was also required for efficient replication of HIV-1 in some cell types and that the restriction factor counteracted by Vpu was a protein located at cell surface [16, 98-101]. This factor was found to be IFNα-inducible and showed the ability to block the release of Vpu-defective virions by directly tethering them to the plasma membrane of virus-producer cells. The trapped virions are subsequently internalized by endocytosis and probably degraded in lysosomes [83, 85]. Remarkably, the lipid rafts localization of tetherin is coincident with the preferential site for budding and egress of enveloped viruses [102, 103], providing further explanation for the mechanism by which tetherin blocks virion release. Several aspects of the Vpu-mediated antagonism of tetherin are still controversial. It was initially proposed that Vpu impairs the transport of newly synthetized tetherin by sequestering it within the trans-Golgi network [104-106]. Additionally, Vpu might block the recycling of tetherin after its internalization from the lipid rafts [104, 106, 107]. Finally, it was also proposed that Vpu might directly internalize tetherin from cell membrane [108-110]. Interestingly, it was observed that treatment with proteasomal inhibitors lead to increased levels of tetherin and loss of Vpu-mediated enhancement of HIV-1 release. These results suggest that the Vpu-induced down-regulation of tetherin might at least in part involve proteasomal degradation of the restriction factor [111-113]. The exact mechanisms of tetherin down-modulation from cell surface, intracellular sequestration or degradation remain to be determined. These three distinct mechanisms may act cooperatively counteracting tetherin to varying degrees in different cellular contexts. Regardless the model that is preferentially observed, binding of Vpu to tetherin through TM-TM interaction seems to be crucial for Vpu antagonism of the restriction factor [108, 111, 114, 115].

Despite the wide cellular distribution of tetherin and the need to counteract its viral restriction action, most primate lentiviruses do not contain a vpu gene. Some (e.g. SIVsmm, SIVmac, and SIVagm) use their Nef proteins to antagonize tetherin function [116-118]. This is not surprising since Nef protein - a myristoylated protein coded by nef gene essential for HIV replication in vivo - is known to act as an adaptor protein interacting with different cellular proteins. Through these interactions Nef manipulates cellular trafficking, signal transduction and gene expression in HIV infected cells (reviewed in [119]). Apparently, Nef targets the cytoplasmic tail of tetherin reducing its expression at host cell membrane [116, 118]. In alternative to Nef, HIV-2 relies on its envelope glycoprotein Env to antagonize tetherin. The proposed mechanism suggests that Env interacts directly with the ectodomain of tetherin, sequestering it away from sites of virus budding and targeting it to clathrin-mediated endocytosis [120].

Besides the referred lentiviruses, the antiviral activity of tetherin was also demonstrated against a broad range of unrelated viruses, such as filoviruses [87, 88], arenaviruses [88] and herpesviruses [121, 122]. For some of these viruses specific viral encoded antagonists has been described. For example, human herpesviruses 8 (HHV-8, also known as Kaposi's Sarcoma herpesvirus) uses K5/MIR2 - a viral protein belonging to the membrane-associated RING-CH ubiquitin ligase family - to ubiquitinate tetherin and target it for degradation [121]. In Ebola virus - a filovirus associated with hemorrhagic fever outbreaks - the tetherin-mediated restriction is counteracted by viral envelope glycoprotein [123] in a process similar to the described sequestration of tetherin by HIV-2 Env.

4.4. SAMHD1

Myeloid-lineage cells, including monocytes, dendritic cells (DCs) and macrophages, play a multifaceted role in HIV-1 initial infection and viral dissemination during acute infection. In particular, the interactions between HIV and DCs are connected with all aspects of HIV infection in vivo, including transmission, pathogenesis and immune control (recently reviewed in [124]). DCs exposed to HIV during sexual transmission help viral dissemination and systemic infection by two distinct mechanisms: by becoming productively infected or by transferring HIV to CD4+ T cells during immunologic synapse (IS), even in the absence of DCs infection [125-127].

Although DCs can be infected, HIV replication is generally less productive compared with CD4+ T cells. Nevertheless, extensive viral replication takes place once DCs come into contact with CD4+ T cells in lymphoid tissue in the context of IS [128]. This implies that HIV must be able to evade DC’s innate immune sensing and endolysosomal degradation and then make use of DC maturation and migration to draining lymph nodes to be transmitted to highly susceptible T cells during antigen presentation process within lymph nodes (reviewed in [129]).

Infection by DNA or RNA viruses triggers innate immune responses when host recognizes specific viral molecular structures (e.g. nucleic acid and surface glycoprotein), called pattern-associated molecular patterns (PAMPs) [130-132]. These PAMPs are recognized by pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), RIG-I-like helicases (RLH), and cytosolic DNA sensor proteins. Inside the cytoplasm, viral nucleic acid can be detected by different PRRs depending on the cell type. For example, TLR7 and TLR9 are responsible for detection of viral RNA and DNA, respectively, in plasmacytoid dendritic cells (pDCs), whereas RLHs detect viral RNA in conventional DCs, macrophages and fibroblasts [133, 134]. The recognition of PAMPs by the PRRs activates several transcription factors, namely nuclear factor-κappa binding (NF-κB) and IFN regulatory factors (IRFs). This activation leads to the production of pro-inflammatory cytokines and type-I IFNs (IFN-α and IFN-β), respectively (reviewed in [130]). The production of type-I IFNs induces the expression of hundreds of interferon-stimulated genes (ISGs) [135], providing crucial mechanisms of antiviral defense by inhibiting viral replication and spread. For example, during HIV Infection, viral single-stranded RNA (ssRNA) is recognized by TLR7/8 initiating anti-HIV immune response by inducing type I IFN. However, as a well-adapted human pathogen HIV must be able to avoid – at least in part – these cell sensing mechanisms in order to evade host innate immunity.

Sterile alpha motif (SAM) and histidine/aspartic acid (HD) domain-containing protein 1 (SAMHD1), an analogue of the murine IFN-y-induced gene Mg11 [136], was identified as a HIV-1 restriction factor that blocks early-stage virus replication in DCs and other myeloid cells [137, 138]. It acts by depleting the intracellular pool of deoxynucleoside triphosphates (dNTP), thus impairing HIV-1 reverse transcription and productive infection [139-141]. The expected lower replication in DCs may enable HIV-1 to avoid intracellular viral sensor that would otherwise trigger IFN-mediated antiviral immunity [142, 143]. It seems that while SAMHD1 effectively renders DCs less permissive to HIV-1 infection, it is somewhat paradoxically responsible for the HIV-1 evasion of immune sensing and subsequent poor priming of adaptive immunity.

HIV-2 brings in a new and interesting element: Vpx (an accessory protein encoded by vpx gene, present in SIVsm/SIVmac and HIV-2), that is believed to have originated by duplication of the common vpr gene present in primate lentiviruses [144], possibly to compensate for a theorised low HIV-2 RT affinity for dNTPs [145, 146]. This accessory protein antagonizes the effect of SAMHD1 by targeting it for proteasomal degradation using the host cell E3 ubiquitin ligase complex, in which Vpx interacts with the DCAF1 subunit of the CUL4A/DDB1 ubiquitin ligase to degrade SAMHD1 via the proteasome [137, 139, 147, 148]. The degradation of SAMHD1 renders HIV-2-infected DCs much more permissive to productive infection and viral replication, allowing faster accumulation of full length viral DNA [148]. This results in a widely positive DC-specific effect in the innate immune sensing of HIV-2 infection [143, 146, 148, 149] and it may be related to the lower viral load and slower progression to AIDS that is characteristic of HIV-2 infection (reviewed in [150]). The immunologically positive effects of Vpx was also demonstrated in monocyte-derived DCs (MMDCs) infected with HIV-1 where an increased type I IFN production and up-regulation of CD86 was only observed in the presence of Vpx [146]. Hence, by avoiding productive infection of MDDCs through preservation of SAMHD1 function, HIV-1 may also control viral antigen presentation, resulting in qualitatively or quantitatively minor CD8+ and CD4+ responses [146, 149, 151]. Furthermore, individuals with low SAMHD1 activity or silenced SAMHD1, present an enhanced immune response to HIV-1 infection, as previously hypothesised [139, 143] [139, 143] and demonstrated [146].

4.5. MxB

The myxovirus resistance (Mx) genes were discovered in the 1960s when it was observed that wild mice were resistant to influenza viruses, whereas inbred mice were susceptible [152]. This trait was later mapped to a locus on mouse chromosome 16 [153-156]. Mx family proteins are found in almost all vertebrates, demonstrating their evolutionary importance for host organisms [157]. Humans Mx gene resides on chromossome 21 [158] and encodes two proteins, called MxA and MxB, that belong to the family of dynamin-like large GTPases. The MxA protein has been recognized as a potent cell restriction factor with antiviral activity against pathogenic DNA and RNA viruses [159].

The X-ray crystal structure of human MxA showed that this protein can be divided into a globular GTPase head, a largely C-terminal α-helical stalk domain and a series of α-helices found in sequences adjacent to these domains which fold in the protein tertiary structure to form the bundle signaling element (BSE) [160]. On the basis of sequence homology and computer modeling the predicted structure of MxB is almost superimposable with that of MxA, having 63% amino acid sequence identity.

In contrast to human MxA protein that inhibits a variety of viruses [161], MxB was initially described as lacking antiviral activity against influenza or vesicular stomatitis virus [162]. Instead, MxB was solely related to cellular functions, such as regulating nuclear import and cell-cycle progression [163, 164].

This view was challenged in 2011, when Schoggings and collaborators addressed an overexpression screening to test the antiviral activity of more than 380 human interferon stimulated gene (ISGs) products against a panel of viruses, where they first uncovered an antiviral activity of human MxB against HIV-1 [165].

More recently, three additional studies [166-168] showed that MxB overexpression potently reduces the permissiveness of the cells in a single-cycle HV-1 infection assay. They also demonstrate that silencing MxB expression reduced the inhibitory potency of the interferon-α demonstrating its importance in the interferon-mediated response against the early steps of HIV-1 infection.

The next step was to understand which specific post-entry event of the HIV replication cycle was affected by MxB expression. Recent studies agreed that MxB expression potently inhibited HIV-1 infection after reverse transcription but before integration [166-168]. So MxB might be interfering with one or more of the following processes: 1) HIV-1 uncoating; 2) nuclear import of the HIV-1 PIC; or 3) nuclear maturation of the PIC.

Fricke and colleagues [169] suggested a model in which MxB binds to the HIV-1 core in the cytoplasm of the cell and prevents the uncoating process of HIV-1 through stabilization of incoming viral capsides. In addition, they demonstrated that MxB requires capsid binding and oligomerization for effective restriction.

More recently, Matreyek et al. [170] observed that MxB restricts HIV-1 after DNA synthesis at steps that are coincident with PIC nuclear import and integration.

HIV-1 RNA is reverse transcribed into double stranded linear DNA and carries a fraction of the viron CA protein [171, 172]. HIV-1 CA protein is known to play a central role in mediating physical interactions with several host proteins involved in the post-entry step of infection. Some identified residues of CA involved in binding to cyclophilin A (CypA), TRIM5α, TNP03, CPSF6, NUP153 and NUP358/RanBP2 are also critical for the sensitivity of HIV-1 to the antiviral action of MxB. Results obtained by Liu and colleagues indicate that both silencing of CypA expression or disruption of the CA-CypA interaction by addition of cyclosporine A abrogated the antiviral activity of MxB, thus CypA binding to the HIV-1 CA appears to be required for MXB restriction. Furthermore, results obtained by diverse groups indicate that CA mutations counteracted MxB restriction [165-168, 170].

The viral integrase (IN) protein processes the long terminal repeat (LTR) ends of the viral DNA to yield the integration-competent PIC, which subsequently transports the viral DNA into the nucleus for IN-mediated integration [173]. Matreyek and collaborators [170] found evidence for an additional block in the formation of 2-LTR circular viral DNA (that are only present in the nucleus, and thus have been utilized as a marker of nuclear entry of viral DNA [174]). In contrast, results obtained by Liu and collaborators [167] showed that MxB reduces the levels of integrated HIV-1 DNA, though it does not affect the amount of 2-LTR circles. They concluded that MxB impairs the integration step and spares the nuclear entry of viral DNA.

Apparently, MxB antiviral activity is independent of its GTPase active site residues or stalk domain Loop4 (both previously shown to be necessary for MxA function) that confer functional oligomerization to related dynamin family proteins [166, 168]. There are two locations in MxB that exhibit the greatest sequence dissimilarity with MxA. The first one is Loop4 that is not critical for MxB antiviral activity but is important for the MxA inhibition of Influenza A and Thogotovirus infection [170, 175]. The other part of MxB with greatest dissimilarity to MxA is the N-terminal region. The specific particular functions conferred by this region are particularly important for MxB activity and consequent HIV-1 restriction [170].

In a global perspective, the post-entry step of HIV-1 replication cycle appears to be quite vulnerable to the actions of IFN-inducible restriction factors: TRIM5α, APOBEC3 proteins, SAMHD1 and, more recently, MxB use distinct mechanisms to prevent integration of this pathogenic virus in host genome. Certainly it will continue to be of interest to the scientific community the study of restriction factors of viral infection by antiviral host factors due to its impact in many areas. These findings raises hope as a potential clinical and epidemiological relevant approach which could be exploited to control HIV infections and AIDS.

4.6. Cholesterol-25-hydroxylase

Recently, a new antiviral IFN-induced protein (cholesterol 25-hydroxilase; CH25H) was identified as being able to block the fusion between viral envelope and target cell membrane. It exhibits a broadly antiviral activity against several enveloped virus including HIV, Ebola virus (Zaire strain), vesicular stomatitis virus, herpes simplex virus I, Rift Valley fever virus, Nipah virus, Influenza A (H1N1) virus and varicella zoster virus [176, 177]. It also revealed antiviral effect against poliovirus [178], a non-enveloped virus. The IFN-induced cholesterol-25-hydroxylase (Ch25h) gene encodes an endoplasmic-reticulum-associated enzyme (CH25H) that mediates the oxidation of cholesterol, by the addition of an extra hydroxyl group at position 25, converting it to 25-hydroxycholesterol (25HC). 25HC belongs to a large class of endogenous cholesterol derivatives named oxysterols. In addition to their involvement in basic metabolic processes, e.g. bile acids production in the liver [179], oxysterols also play a key role in several signaling pathways that influence the activation of macrophages, T-cells and B-cells, and thus the regulation of inflammatory response [177, 180-188].

Although several antiviral mechanisms have been suggested for CH25H and 25HC, they seem to inhibited HIV-1 replication by blocking the virus-cell fusion step [176]. One possible mechanism underlying this effect is the induction of cellular membrane changes affecting the topology and permissiveness for fusion of host cell membrane. There is extensive evidence that the lipid composition of target cell membrane influences HIV-1 fusion and entry. In fact, though the fusion event is triggered by HIV envelope glycoproteins, lipids also play a key role in virus-cell membrane fusion by themselves, directly affecting the viral receptor accessibility and distribution in lipid rafts domains of the plasma membrane, or the membrane fluidity and curvature [189]. The modifications in cellular membrane architecture induced by 25HC (considerably more hydrophilic than cholesterol [190]) would be of outstanding importance in the complex protein-lipid interplay required for successful virus-cell fusion events [176].


5. Conclusion

The pathogenesis of HIV infection is a highly complex network of interconnected processes. It likely borrows much of its complexity from the co-evolution with several mammalian species that HIV and predecessors lentiviruses have enjoyed over an unknown, but rather long period of time. During the complex interplay between HIV and host cell, different intrinsic cell factors are involved that mitigate or restrict HIV replication and spread as shown in Figure 3. Some of these host restrictions factors that have been identified inhibit early steps of replication cycle. In fact, the post-entry step of HIV-1 replication cycle appears to be quite vulnerable to the actions of IFN-inducible restriction factors: TRIM5α, APOBEC3 proteins, SAMHD1 and, more recently, MxB and cholesterol 25-hydroxylase, all of them use distinct mechanisms to prevent integration of viral DNA into host genome. The best characterized of these are the TRIM5α and the APOBEC3 proteins. APOBEC3 interacts with the nascent DNA during reverse transcription while TRIM5α interacts with incoming viral capsids resulting in premature disassembly. SAMHD1 protein acts prior to integration, by depleting the intracellular pool of deoxynucleoside triphosphates (dNTP), therefore impairing HIV-1 reverse transcription and accumulation of HIV double stranded DNA. Another restriction factor, Tetherin (BST- 2/CD317), acts in late steps of viral replication cycle, by preventing viruses from leaving the cell during budding and release of viral particles. The recently described factors MxB and cholesterol 25-hydroxylase seem to inhibit the nuclear import/integration of viral DNA and the viral fusion events, respectively. Remarkably, despite this array of restriction factors, HIV had created viral proteins to subdue these restrictions emphasizing how well adapted this virus is to human host.

Figure 3.

Schematic representation of a simplified replication cycle of HIV and the different steps that are blocked by cellular restriction factors. The cholesterol-25-hydroxylase blocks viral fusion with target cell membrane; TRIM5α, SAMHD1 and APOBEC3G impair viral DNA synthesis either by accelerating capsid disintegration, reducing dNTPs intracellular pool or by introducing mutations in nascent chain of viral DNA; MxB impairs the nuclear import and/or the integration step; and finally, Tetherin induces virion retention at the host-cell membrane.

Finally, the identification of cellular restriction factors, such as those referred in this chapter, and the disclosure of the mechanisms by which they impede viral replication, also enabled the identification of new promising targets for therapeutic intervention. In fact, it is increasingly clear that the most successful treatment and/or prevention strategies will likely be derived from the modulation of human cell functions rather than acting directly upon viral mechanisms.



This work was supported by grants from Fundação para a Ciência e Tecnologia and Ministério da Saúde de Portugal (VIH/SAU/0006/2011) and from Gilead Sciences Portugal (Programa Gilead Génese).


  1. 1. Melikyan GB. HIV entry: a game of hide-and-fuse? Current Opinion in Virology 2014;4:1–7.
  2. 2. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996;272:1955–8.
  3. 3. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996;272:872–7.
  4. 4. Clapham PR, McKnight A. Cell surface receptors, virus entry and tropism of primate lentiviruses. The Journal of General Virology 2002;83:1809–29.
  5. 5. Doms RW, Trono D. The plasma membrane as a combat zone in the HIV battlefield. Genes & Development 2000;14:2677–88.
  6. 6. Marsh M, Helenius A. Virus entry: open sesame. Cell 2006;124:729–40.
  7. 7. Miyauchi K, Kim Y, Latinovic O, Morozov V, Melikyan GB. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell 2009;137:433–44.
  8. 8. Suzuki Y, Craigie R. The road to chromatin - nuclear entry of retroviruses. Nature Reviews Microbiology 2007;5:187–96.
  9. 9. Strebel K. Virus-host interactions: role of HIV proteins Vif, Tat, and Rev. Aids 2003;17 Suppl 4:S25–34.
  10. 10. Gelderblom HR. Assembly and morphology of HIV: potential effect of structure on viral function. Aids 1991;5:617–37.
  11. 11. Zhang Y, Qian H, Love Z, Barklis E. Analysis of the assembly function of the human immunodeficiency virus type 1 gag protein nucleocapsid domain. Journal of Virology 1998;72:1782–9.
  12. 12. Meng B, Lever AM. Wrapping up the bad news - HIV assembly and release. Retrovirology 2013;10:5.
  13. 13. Frankel AD, Young JAT. HIV-1: Fifteen Proteins and an RNA. Annual Review of Biochemistry 1998;67:1–25.
  14. 14. Strebel K. HIV accessory proteins versus host restriction factors. Current Opinion in Virology 2013;3:692–9.
  15. 15. Desimmie BA, Delviks-Frankenberrry KA, Burdick RC, Qi D, Izumi T, Pathak VK. Multiple APOBEC3 restriction factors for HIV-1 and one Vif to rule them all. Journal of Molecular Biology 2014;426:1220–45.
  16. 16. Dubé M, Bego MG, Paquay C, Cohen EA. Modulation of HIV-1-host interaction: role of the Vpu accessory protein. Retrovirology 2010;7:114.
  17. 17. Guenzel CA, Hérate C, Benichou S. HIV-1 Vpr-a still “enigmatic multitasker.” Frontiers in Microbiology 2014;5:127.
  18. 18. Pollard VW, Malim MH. The HIV-1 Rev protein. Annual Review of Microbiology 1998;52:491–532.
  19. 19. Aiken C, Konner J, Landau NR, Lenburg ME, Trono D. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 1994;76:853–64.
  20. 20. Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 1998;391:397–401.
  21. 21. Kirchhoff F, Schindler M, Specht A, Arhel N, Munch J. Role of Nef in primate lentiviral immunopathogenesis. Cellular and Molecular Life Sciences : CMLS 2008;65:2621–36.
  22. 22. Bieniasz PD. Intrinsic immunity: a front-line defense against viral attack. Nature Immunology 2004;5:1109–15.
  23. 23. Pitha PM. Innate antiviral response: role in HIV-1 infection. Viruses 2011;3:1179–203.
  24. 24. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. Journal of Virology 2009;83:3719–33.
  25. 25. Malleret B, Manéglier B, Karlsson I, Lebon P, Nascimbeni M, Perié L, et al. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression. Blood 2008;112:4598–608.
  26. 26. Kornbluth RS, Oh PS, Munis JR, Cleveland PH, Richman DD. Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro. The Journal of Experimental Medicine 1989;169:1137–51.
  27. 27. Meylan PR, Guatelli JC, Munis JR, Richman DD, Kornbluth RS. Mechanisms for the inhibition of HIV replication by interferons-alpha, -beta, and -gamma in primary human macrophages. Virology 1993;193:138–48.
  28. 28. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski JG. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 2004;427:848–53.
  29. 29. Grütter MG, Luban J. TRIM5 structure, HIV-1 capsid recognition, and innate immune signaling. Current Opinion in Virology 2012;2:142–50.
  30. 30. Sayah DM, Sokolskaja E, Berthoux L, Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 2004;430:569–73.
  31. 31. Keckesova Z, Ylinen LMJ, Towers GJ. The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities. Proceedings of the National Academy of Sciences of the United States of America 2004;101:10780–5.
  32. 32. Perez-Caballero D, Hatziioannou T, Yang A, Cowan S, Bieniasz PD. Human tripartite motif 5alpha domains responsible for retrovirus restriction activity and specificity. Journal of Virology 2005;79:8969–78.
  33. 33. Asaoka K, Ikeda K, Hishinuma T, Horie-Inoue K, Takeda S, Inoue S. A retrovirus restriction factor TRIM5alpha is transcriptionally regulated by interferons. Biochemical and Biophysical Research Communications 2005;338:1950–6.
  34. 34. Sastri J, Campbell EM. Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction. AIDS Research and Human Retroviruses 2011;27:231–8.
  35. 35. Yamauchi K, Wada K, Tanji K, Tanaka M, Kamitani T. Ubiquitination of E3 ubiquitin ligase TRIM5 alpha and its potential role. The FEBS Journal 2008;275:1540–55.
  36. 36. Lienlaf M, Hayashi F, Di Nunzio F, Tochio N, Kigawa T, Yokoyama S, et al. Contribution of E3-ubiquitin ligase activity to HIV-1 restriction by TRIM5alpha(rh): structure of the RING domain of TRIM5alpha. Journal of Virology 2011;85:8725–37.
  37. 37. Diaz-Griffero F, Qin X-R, Hayashi F, Kigawa T, Finzi A, Sarnak Z, et al. A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction. Journal of Virology 2009;83:10737–51.
  38. 38. Sawyer SL, Wu LI, Emerman M, Malik HS. Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain. Proceedings of the National Academy of Sciences of the United States of America 2005;102:2832–7.
  39. 39. Song B, Gold B, O'Huigin C, Javanbakht H, Li X, Stremlau M, et al. The B30.2(SPRY) domain of the retroviral restriction factor TRIM5alpha exhibits lineage-specific length and sequence variation in primates. Journal of Virology 2005;79:6111–21.
  40. 40. Stremlau M, Perron M, Welikala S, Sodroski JG. Species-specific variation in the B30.2(SPRY) domain of TRIM5alpha determines the potency of human immunodeficiency virus restriction. Journal of Virology 2005;79:3139–45.
  41. 41. Ohkura S, Yap MW, Sheldon T, Stoye JP. All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction. Journal of Virology 2006;80:8554–65.
  42. 42. Chatterji U, Bobardt MD, Gaskill P, Sheeter D, Fox H, Gallay PA. Trim5alpha accelerates degradation of cytosolic capsid associated with productive HIV-1 entry. The Journal of Biological Chemistry 2006;281:37025–33.
  43. 43. Anderson JL, Campbell EM, Wu X, Vandegraaff N, Engelman A, Hope TJ. Proteasome inhibition reveals that a functional preintegration complex intermediate can be generated during restriction by diverse TRIM5 proteins. Journal of Virology 2006;80:9754–60.
  44. 44. Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ. Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection. Proceedings of the National Academy of Sciences of the United States of America 2006;103:7465–70.
  45. 45. Maegawa H, Miyamoto T, Sakuragi J-I, Shioda T, Nakayama EE. Contribution of RING domain to retrovirus restriction by TRIM5alpha... - PubMed - NCBI. Virology 2010;399:212–20.
  46. 46. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, et al. DNA deamination mediates innate immunity to retroviral infection. Cell 2003;113:803–9.
  47. 47. Liddament MT, Brown WL, Schumacher AJ, Harris RS. APOBEC3F properties and hypermutation preferences indicate activity against HIV-1 in vivo. Current Biology : CB 2004;14:1385–91.
  48. 48. Wiegand HL, Doehle BP, Bogerd HP, Cullen BR. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. The EMBO Journal 2004;23:2451–8.
  49. 49. Zheng Y-H, Irwin D, Kurosu T, Tokunaga K, Sata T, Peterlin BM. Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication. Journal of Virology 2004;78:6073–6.
  50. 50. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 2002;418:646–50.
  51. 51. Farrow MA, Kim E-Y, Wolinsky SM, Sheehy AM. NFAT and IRF proteins regulate transcription of the anti-HIV gene, APOBEC3G. The Journal of Biological Chemistry 2011;286:2567–77.
  52. 52. Rose KM, Marin M, Kozak SL, Kabat D. Transcriptional regulation of APOBEC3G, a cytidine deaminase that hypermutates human immunodeficiency virus. The Journal of Biological Chemistry 2004;279:41744–9.
  53. 53. Alce TM, Popik W. APOBEC3G is incorporated into virus-like particles by a direct interaction with HIV-1 Gag nucleocapsid protein. The Journal of Biological Chemistry 2004;279:34083–6.
  54. 54. Cen S, Guo F, Niu M, Saadatmand J, Deflassieux J, Kleiman L. The interaction between HIV-1 Gag and APOBEC3G. The Journal of Biological Chemistry 2004;279:33177–84.
  55. 55. Schäfer A, Bogerd HP, Cullen BR. Specific packaging of APOBEC3G into HIV-1 virions is mediated by the nucleocapsid domain of the gag polyprotein precursor. Virology 2004;328:163–8.
  56. 56. Zennou V, Perez-Caballero D, Göttlinger H, Bieniasz PD. APOBEC3G incorporation into human immunodeficiency virus type 1 particles. Journal of Virology 2004;78:12058–61.
  57. 57. Luo K, Liu B, Xiao Z, Yu Y, Yu X, Gorelick R, et al. Amino-terminal region of the human immunodeficiency virus type 1 nucleocapsid is required for human APOBEC3G packaging. Journal of Virology 2004;78:11841–52.
  58. 58. Soros VB, Yonemoto W, Greene WC. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H. PLoS Pathogens 2007;3:e15.
  59. 59. Lecossier D, Bouchonnet F, Clavel F, Hance AJ. Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 2003;300:1112–2.
  60. 60. Iwatani Y, Chan DSB, Wang F, Maynard KS, Sugiura W, Gronenborn AM, et al. Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G. Nucleic Acids Research 2007;35:7096–108.
  61. 61. Mbisa JL, Barr R, Thomas JA, Vandegraaff N, Dorweiler IJ, Svarovskaia ES, et al. Human immunodeficiency virus type 1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration. Journal of Virology 2007;81:7099–110.
  62. 62. Luo K, Wang T, Liu B, Tian C, Xiao Z, Kappes J, et al. Cytidine deaminases APOBEC3G and APOBEC3F interact with human immunodeficiency virus type 1 integrase and inhibit proviral DNA formation. Journal of Virology 2007;81:7238–48.
  63. 63. Bishop KN, Holmes RK, Sheehy AM, Davidson NO, Cho S-J, Malim MH. Cytidine deamination of retroviral DNA by diverse APOBEC proteins. Current Biology : CB 2004;14:1392–6.
  64. 64. Langlois M-A, Beale RCL, Conticello SG, Neuberger MS. Mutational comparison of the single-domained APOBEC3C and double-domained APOBEC3F/G anti-retroviral cytidine deaminases provides insight into their DNA target site specificities. Nucleic Acids Research 2005;33:1913–23.
  65. 65. Mariani R, Chen D, Schrofelbauer B, Navarro F, Konig R, Bollman B, et al. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 2003;114:21–31.
  66. 66. Madani N, Kabat D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein. Journal of Virology 1998;72:10251–5.
  67. 67. Sheehy AM, Gaddis NC, Malim MH. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nature Medicine 2003;9:1404–7.
  68. 68. Marin M, Rose KM, Kozak SL, Kabat D. HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nature Medicine 2003;9:1398–403.
  69. 69. Mehle A, Strack B, Ancuta P, Zhang C, McPike M, Gabuzda D. Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway. The Journal of Biological Chemistry 2004;279:7792–8.
  70. 70. Simon JH, Miller DL, Fouchier RA, Soares MA, Peden KW, Malim MH. The regulation of primate immunodeficiency virus infectivity by Vif is cell species restricted: a role for Vif in determining virus host range and cross-species transmission. The EMBO Journal 1998;17:1259–67.
  71. 71. Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, et al. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 2003;302:1056–60.
  72. 72. Stopak K, de Noronha C, Yonemoto W, Greene WC. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Molecular Cell 2003;12:591–601.
  73. 73. Kobayashi M, Takaori-Kondo A, Miyauchi Y, Iwai K, Uchiyama T. Ubiquitination of APOBEC3G by an HIV-1 Vif-Cullin5-Elongin B-Elongin C complex is essential for Vif function. The Journal of Biological Chemistry 2005;280:18573–8.
  74. 74. Kao S, Khan MA, Miyagi E, Plishka R, Buckler-White A, Strebel K. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity. Journal of Virology 2003;77:11398–407.
  75. 75. Koning FA, Goujon C, Bauby H, Malim MH. Target Cell-Mediated Editing of HIV-1 cDNA by APOBEC3 Proteins in Human Macrophages. Journal of Virology 2011;85:13448–52.
  76. 76. Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, et al. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 2010;143:789–801.
  77. 77. Lee K, Ambrose Z, Martin TD, Oztop I, Mulky A, Julias JG, et al. Flexible use of nuclear import pathways by HIV-1. Cell Host & Microbe 2010;7:221–33.
  78. 78. Swanson CM, Malim MH. SnapShot: HIV-1 proteins. Cell 2008;133:742, 742.e1.
  79. 79. Yan N, Cherepanov P, Daigle JE, Engelman A, Lieberman J. The SET complex acts as a barrier to autointegration of HIV-1. PLoS Pathogens 2009;5:e1000327.
  80. 80. Doehle BP, Schäfer A, Wiegand HL, Bogerd HP, Cullen BR. Differential sensitivity of murine leukemia virus to APOBEC3-mediated inhibition is governed by virion exclusion. Journal of Virology 2005;79:8201–7.
  81. 81. Yu Q, Chen D, König R, Mariani R, Unutmaz D, Landau NR. APOBEC3B and APOBEC3C are potent inhibitors of simian immunodeficiency virus replication. The Journal of Biological Chemistry 2004;279:53379–86.
  82. 82. Doehle BP, Schäfer A, Cullen BR. Human APOBEC3B is a potent inhibitor of HIV-1 infectivity and is resistant to HIV-1 Vif. Virology 2005;339:281–8.
  83. 83. Neil SJD, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 2008;451:425–30.
  84. 84. Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host & Microbe 2008;3:245–52.
  85. 85. Neil SJD, Sandrin V, Sundquist WI, Bieniasz PD. An interferon-alpha-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host & Microbe 2007;2:193–203.
  86. 86. Blasius AL, Giurisato E, Cella M, Schreiber RD, Shaw AS, Colonna M. Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naive mouse, but a promiscuous cell surface antigen following IFN stimulation. Journal of Immunology 2006;177:3260–5.
  87. 87. Jouvenet N, Neil SJD, Zhadina M, Zang T, Kratovac Z, Lee Y, et al. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. Journal of Virology 2009;83:1837–44.
  88. 88. Sakuma T, Noda T, Urata S, Kawaoka Y, Yasuda J. Inhibition of Lassa and Marburg virus production by tetherin. Journal of Virology 2009;83:2382–5.
  89. 89. Groom HCT, Yap MW, Galão RP, Neil SJD, Bishop KN. Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors. Proceedings of the National Academy of Sciences of the United States of America 2010;107:5166–71.
  90. 90. Arnaud F, Black SG, Murphy L, Griffiths DJ, Neil SJ, Spencer TE, et al. Interplay between ovine bone marrow stromal cell antigen 2/tetherin and endogenous retroviruses. Journal of Virology 2010;84:4415–25.
  91. 91. Mattiuzzo G, Ivol S, Takeuchi Y. Regulation of porcine endogenous retrovirus release by porcine and human tetherins. Journal of Virology 2010;84:2618–22.
  92. 92. Vidal-Laliena M, Romero X, March S, Requena V, Petriz J, Engel P. Characterization of antibodies submitted to the B cell section of the 8th Human Leukocyte Differentiation Antigens Workshop by flow cytometry and immunohistochemistry. Cellular Immunology 2005;236:6–16.
  93. 93. Zheng Y-H, Jeang KT, Tokunaga K. Host restriction factors in retroviral infection: promises in virus-host interaction. Retrovirology 2012;9:112.
  94. 94. Kupzig S, Korolchuk V, Rollason R, Sugden A, Wilde A, Banting G. Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic 2003;4:694–709.
  95. 95. Rollason R, Korolchuk V, Hamilton C, Jepson M, Banting G. A CD317/tetherin-RICH2 complex plays a critical role in the organization of the subapical actin cytoskeleton in polarized epithelial cells. The Journal of Cell Biology 2009;184:721–36.
  96. 96. Masuyama N, Kuronita T, Tanaka R, Muto T, Hirota Y, Takigawa A, et al. HM1.24 is internalized from lipid rafts by clathrin-mediated endocytosis through interaction with alpha-adaptin. The Journal of Biological Chemistry 2009;284:15927–41.
  97. 97. Willey RL, Maldarelli F, Martin MA, Strebel K. Human immunodeficiency virus type 1 Vpu protein regulates the formation of intracellular gp160-CD4 complexes. Journal of Virology 1992;66:226–34.
  98. 98. Sakai H, Tokunaga K, Kawamura M, Adachi A. Function of human immunodeficiency virus type 1 Vpu protein in various cell types. The Journal of General Virology 1995;76 (Pt 11):2717–22.
  99. 99. Geraghty RJ, Talbot KJ, Callahan M, Harper W, Panganiban AT. Cell type-dependence for Vpu function. Journal of Medical Primatology 1994;23:146–50.
  100. 100. Varthakavi V, Smith RM, Bour SP, Strebel K, Spearman P. Viral protein U counteracts a human host cell restriction that inhibits HIV-1 particle production. Proceedings of the National Academy of Sciences 2003;100:15154–9.
  101. 101. Neil SJD, Eastman SW, Jouvenet N, Bieniasz PD. HIV-1 Vpu promotes release and prevents endocytosis of nascent retrovirus particles from the plasma membrane. PLoS Pathogens 2006;2:e39.
  102. 102. Aloia RC, Tian H, Jensen FC. Lipid composition and fluidity of the human immunodeficiency virus envelope and host cell plasma membranes. Proceedings of the National Academy of Sciences of the United States of America 1993;90:5181–5.
  103. 103. Panchal RG, Ruthel G, Kenny TA, Kallstrom GH, Lane D, Badie SS, et al. In vivo oligomerization and raft localization of Ebola virus protein VP40 during vesicular budding. Proceedings of the National Academy of Sciences 2003;100:15936–41.
  104. 104. Dubé M, Roy BB, Guiot-Guillain P, Binette J, Mercier J, Chiasson A, et al. Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment. PLoS Pathogens 2010;6:e1000856.
  105. 105. Andrew AJ, Miyagi E, Strebel K. Differential effects of human immunodeficiency virus type 1 Vpu on the stability of BST-2/tetherin. Journal of Virology 2011;85:2611–9.
  106. 106. Lau D, Kwan W, Guatelli J. Role of the endocytic pathway in the counteraction of BST-2 by human lentiviral pathogens. Journal of Virology 2011;85:9834–46.
  107. 107. Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A, et al. Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. PLoS Pathogens 2009;5:e1000450.
  108. 108. Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, et al. HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes. The Journal of Biological Chemistry 2009;284:35060–72.
  109. 109. Iwabu Y, Fujita H, Tanaka Y, Sata T, Tokunaga K. Direct internalization of cell-surface BST-2/tetherin by the HIV-1 accessory protein Vpu. Communicative & Integrative Biology 2010;3:366–9.
  110. 110. Janvier K, Pelchen-Matthews A, Renaud J-B, Caillet M, Marsh M, Berlioz-Torrent C. The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation. PLoS Pathogens 2011;7:e1001265.
  111. 111. Gupta RK, Hué S, Schaller T, Verschoor E, Pillay D, Towers GJ. Mutation of a single residue renders human tetherin resistant to HIV-1 Vpu-mediated depletion. PLoS Pathogens 2009;5:e1000443.
  112. 112. Goffinet C, Allespach I, Homann S, Tervo H-M, Habermann A, Rupp D, et al. HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor. Cell Host & Microbe 2009;5:285–97.
  113. 113. Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V. HIV-1 Vpu Neutralizes the Antiviral Factor Tetherin/BST-2 by Binding It and Directing Its Beta-TrCP2-Dependent Degradation. PLoS Pathogens 2009;5:e1000574.
  114. 114. McNatt MW, Zang T, Hatziioannou T, Bartlett M, Fofana IB, Johnson WE, et al. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. PLoS Pathogens 2009;5:e1000300.
  115. 115. Rong L, Zhang J, Lu J, Pan Q, Lorgeoux R-P, Aloysius C, et al. The transmembrane domain of BST-2 determines its sensitivity to down-modulation by human immunodeficiency virus type 1 Vpu. Journal of Virology 2009;83:7536–46.
  116. 116. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, et al. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. PLoS Pathogens 2009;5:e1000429.
  117. 117. Sauter D, Schindler M, Specht A, Landford WN, Munch J, Kim K-A, et al. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host & Microbe 2009;6:409–21.
  118. 118. Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC, et al. Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host & Microbe 2009;6:54–67.
  119. 119. Basmaciogullari S, Pizzato M. The activity of Nef on HIV-1 infectivity. Frontiers in Microbiology 2014;5:232.
  120. 120. Le Tortorec A, Neil SJD. Antagonism to and intracellular sequestration of human tetherin by the human immunodeficiency virus type 2 envelope glycoprotein. Journal of Virology 2009;83:11966–78.
  121. 121. Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, et al. Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. Journal of Virology 2009;83:9672–81.
  122. 122. Pardieu C, Vigan R, Wilson SJ, Calvi A, Zang T, Bieniasz P, et al. The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin. PLoS Pathogens 2010;6:e1000843.
  123. 123. Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proceedings of the National Academy of Sciences of the United States of America 2009;106:2886–91.
  124. 124. Barroca P, Calado M, Azevedo-Pereira JM. HIV/dendritic cell interaction: consequences in the pathogenesis of HIV infection. AIDS Reviews 2014;16:223–35.
  125. 125. Cameron PU, Freudenthal PS, Barker JM, Gezelter S, Inaba K, Steinman RM. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science 1992;257:383–7.
  126. 126. Pope M, Betjes MG, Romani N, Hirmand H, Cameron PU, Hoffman L, et al. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 1994;78:389–98.
  127. 127. Pope M, Gezelter S, Gallo N, Hoffman L, Steinman RM. Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. The Journal of Experimental Medicine 1995;182:2045–56.
  128. 128. Granelli-Piperno A, Finkel V, Delgado E, Steinman RM. Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. Current Biology : CB 1999;9:21–9.
  129. 129. Wu L, KewalRamani VN. Dendritic-cell interactions with HIV: infection and viral dissemination. Nature Reviews Immunology 2006;6:859–68.
  130. 130. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783–801.
  131. 131. Pichlmair A, Reis e Sousa C. Innate recognition of viruses. Immunity 2007;27:370–83.
  132. 132. Bowie AG, Unterholzner L. Viral evasion and subversion of pattern-recognition receptor signalling. Nature Reviews Immunology 2008;8:911–22.
  133. 133. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 2005;23:19–28.
  134. 134. Kumagai Y, Takeuchi O, Kato H, Kumar H, Matsui K, Morii E, et al. Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses. Immunity 2007;27:240–52.
  135. 135. Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ. INTERFEROME: the database of interferon regulated genes. Nucleic Acids Research 2009;37:D852–7.
  136. 136. Li N, Zhang W, Cao X. Identification of human homologue of mouse IFN-gamma induced protein from human dendritic cells. Immunology Letters 2000;74:221–4.
  137. 137. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Ségéral E, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 2011;474:654–7.
  138. 138. Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 2011;474:658–61.
  139. 139. Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HCT, Rice GI, Christodoulou E, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 2011;480:379–82.
  140. 140. Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nature Immunology 2012;13:223–8.
  141. 141. Kim B, Nguyen LA, Daddacha W, Hollenbaugh JA. Tight interplay among SAMHD1 protein level, cellular dNTP levels, and HIV-1 proviral DNA synthesis kinetics in human primary monocyte-derived macrophages. The Journal of Biological Chemistry 2012;287:21570–4.
  142. 142. Yan N, Lieberman J. Gaining a foothold: how HIV avoids innate immune recognition. Current Opinion in Immunology 2011;23:21–8.
  143. 143. Manel N, Hogstad B, Wang Y, Levy DE, Unutmaz D, Littman DR. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 2010;467:214–7.
  144. 144. Tristem M, Marshall C, Karpas A, Petrik J, Hill F. Origin of vpx in lentiviruses. Nature 1990;347:341–2.
  145. 145. Fujita M, Nomaguchi M, Adachi A, Otsuka M. SAMHD1-Dependent and -Independent Functions of HIV-2/SIV Vpx Protein. Frontiers in Microbiology 2012;3:297.
  146. 146. Puigdomènech I, Casartelli N, Porrot F, Schwartz O. SAMHD1 Restricts HIV-1 Cell-to-Cell Transmission and Limits Immune Detection in Monocyte-Derived Dendritic Cells. Journal of Virology 2013;87:2846–56.
  147. 147. Kaushik R, Zhu X, Stranska R, Wu Y, Stevenson M. A cellular restriction dictates the permissivity of nondividing monocytes/macrophages to lentivirus and gammaretrovirus infection. Cell Host & Microbe 2009;6:68–80.
  148. 148. Goujon C, Rivière L, Jarrosson-Wuilleme L, Bernaud J, Rigal D, Darlix J-L, et al. SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells. Retrovirology 2007;4:2.
  149. 149. Silvin A, Manel N. Interactions between HIV-1 and innate immunity in dendritic cells. Advances in Experimental Medicine and Biology 2013;762:183–200.
  150. 150. Azevedo-Pereira JM. HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic than HIV-1. In: Saxena SK, editor. Current Perspectives in HIV Infection, Croatia: InTech; 2013, pp. 411–45.
  151. 151. Manel N, Littman DR. Hiding in plain sight: how HIV evades innate immune responses. Cell 2011;147:271–4.
  152. 152. Lindenmann J. Resistance of mice to mouse-adapted influenza A virus. Virology 1962;16:203–4.
  153. 153. Haller O, Acklin M, Staeheli P. Influenza virus resistance of wild mice: wild-type and mutant Mx alleles occur at comparable frequencies. Journal of Interferon Research 1987;7:647–56.
  154. 154. Reeves RH, O'Hara BF, Pavan WJ, Gearhart JD, Haller O. Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21. Journal of Virology 1988;62:4372–5.
  155. 155. Staeheli P, Pravtcheva D, Lundin LG, Acklin M, Ruddle F, Lindenmann J, et al. Interferon-regulated influenza virus resistance gene Mx is localized on mouse chromosome 16. Journal of Virology 1986;58:967–9.
  156. 156. Staeheli P, Sutcliffe JG. Identification of a second interferon-regulated murine Mx gene. Molecular and Cellular Biology 1988;8:4524–8.
  157. 157. Verhelst J, Hulpiau P, Saelens X. Mx proteins: antiviral gatekeepers that restrain the uninvited. Microbiology and Molecular Biology Reviews : MMBR 2013;77:551–66.
  158. 158. Aebi M, Fäh J, Hurt N, Samuel CE, Thomis D, Bazzigher L, et al. cDNA structures and regulation of two interferon-induced human Mx proteins. Molecular and Cellular Biology 1989;9:5062–72.
  159. 159. Mänz B, Dornfeld D, Götz V, Zell R, Zimmermann P, Haller O, et al. Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein. PLoS Pathogens 2013;9:e1003279.
  160. 160. Gao S, Malsburg von der A, Dick A, Faelber K, Schröder GF, Haller O, et al. Structure of myxovirus resistance protein a reveals intra- and intermolecular domain interactions required for the antiviral function. Immunity 2011;35:514–25.
  161. 161. Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. Journal of Interferon and Cytokine Research 2011;31:79–87.
  162. 162. Pavlovic J, Zürcher T, Haller O, Staeheli P. Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. Journal of Virology 1990;64:3370–5.
  163. 163. King MC, Raposo G, Lemmon MA. Inhibition of nuclear import and cell-cycle progression by mutated forms of the dynamin-like GTPase MxB. Proceedings of the National Academy of Sciences 2004;101:8957–62.
  164. 164. Melén K, Keskinen P, Ronni T, Sareneva T, Lounatmaa K, Julkunen I. Human MxB protein, an interferon-alpha-inducible GTPase, contains a nuclear targeting signal and is localized in the heterochromatin region beneath the nuclear envelope. The Journal of Biological Chemistry 1996;271:23478–86.
  165. 165. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 2011;472:481–5.
  166. 166. Goujon C, Moncorgé O, Bauby H, Doyle T, Ward CC, Schaller T, et al. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 2013;502:559–62.
  167. 167. Liu Z, Pan Q, Ding S, Qian J, Xu F, Zhou J, et al. The interferon-inducible MxB protein inhibits HIV-1 infection. Cell Host & Microbe 2013;14:398–410.
  168. 168. Kane M, Yadav SS, Bitzegeio J, Kutluay SB, Zang T, Wilson SJ, et al. MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 2013;502:563–6.
  169. 169. Fricke T, White TE, Schulte B, de Souza Aranha Vieira DA, Dharan A, Campbell EM, et al. MxB binds to the HIV-1 core and prevents the uncoating process of HIV-1. Retrovirology 2014;11:68.
  170. 170. Matreyek KA, Wang W, Serrao E, Singh P, Levin HL, Engelman A. Host and viral determinants for MxB restriction of HIV-1 infection. Retrovirology 2014;11:90.
  171. 171. Fassati A, Goff SP. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. Journal of Virology 2001;75:3626–35.
  172. 172. McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG, Emerman M, et al. Visualization of the intracellular behavior of HIV in living cells. The Journal of Cell Biology 2002;159:441–52.
  173. 173. Craigie R, Bushman FD. HIV DNA integration. Cold Spring Harbor Perspectives in Medicine 2012;2:a006890–0.
  174. 174. Bukrinsky MI, Sharova N, Dempsey MP, Stanwick TL, Bukrinskaya AG, Haggerty S, et al. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proceedings of the National Academy of Sciences 1992;89:6580–4.
  175. 175. Mitchell PS, Patzina C, Emerman M, Haller O, Malik HS, Kochs G. Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA. Cell Host & Microbe 2012;12:598–604.
  176. 176. Liu S-Y, Aliyari R, Chikere K, Li G, Marsden MD, Smith JK, et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 2013;38:92–105.
  177. 177. Blanc M, Hsieh WY, Robertson KA, Kropp KA, Forster T, Shui G, et al. The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 2013;38:106–18.
  178. 178. Arita M, Kojima H, Nagano T, Okabe T, Wakita T, Shimizu H. Oxysterol-binding protein family I is the target of minor enviroxime-like compounds. Journal of Virology 2013;87:4252–60.
  179. 179. Schwarz M, Lund EG, Russell DW. Two 7 alpha-hydroxylase enzymes in bile acid biosynthesis. Current Opinion in Lipidology 1998;9:113–8.
  180. 180. Cuthbert JA, Lipsky PE. Sterol metabolism and lymphocyte responsiveness: inhibition of endogenous sterol synthesis prevents mitogen-induced human T cell proliferation. The Journal of Immunology 1981;126:2093–9.
  181. 181. Bauman DR, Bitmansour AD, McDonald JG, Thompson BM, Liang G, Russell DW. 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production. Proceedings of the National Academy of Sciences of the United States of America 2009;106:16764–9.
  182. 182. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 2008;134:97–111.
  183. 183. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 2004;119:299–309.
  184. 184. Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, et al. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Molecular Cell 2003;12:805–16.
  185. 185. Park K, Scott AL. Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons. Journal of Leukocyte Biology 2010;88:1081–7.
  186. 186. Gold ES, Diercks AH, Podolsky I, Podyminogin RL, Askovich PS, Treuting PM, et al. 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. - PubMed - NCBI. Proceedings of the National Academy of Sciences 2014;111:10666–71.
  187. 187. Cyster JG, Dang EV, Reboldi A, Yi T. 25-Hydroxycholesterols in innate and adaptive immunity. Nature Reviews Immunology 2014;14:731–43.
  188. 188. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 2014;345:679–84.
  189. 189. Teissier E, Pécheur E-I. Lipids as modulators of membrane fusion mediated by viral fusion proteins. European Biophysics Journal : EBJ 2007;36:887–99.
  190. 190. Russell DW. Oxysterol biosynthetic enzymes. Biochimica Et Biophysica Acta 2000;1529:126–35.

Written By

J.M. Azevedo-Pereira, Pedro Canhão, Marta Calado, Quirina Santos- Costa and Pedro Barroca

Submitted: 06 June 2014 Published: 02 September 2015