Open access

Immune Responses and Cell Signaling During Chronic HIV Infection

Written By

Abdulkarim Alhetheel, Mahmoud Aly and Marko Kryworuchko

Submitted: 07 May 2012 Published: 10 April 2013

DOI: 10.5772/53010

Chapter metrics overview

2,423 Chapter Downloads

View Full Metrics

1. Introduction

The immune response can be defined by the reaction of the immune system to a particular antigen to which it is exposed. In order to understand immune responses against an infectious agent such as human immunodeficiency virus (HIV) and their regulation during the course of chronic HIV infection, we will provide a brief overview of HIV and its proteins and attempt to shed light on this disease process. We will also review the immune system, its components and describe how these components interact at the molecular levels to fight an invading pathogen such as HIV.


2. Human immunodeficiency virus (HIV)

AIDS (Acquired Immuno-Deficiency Syndrome) in patients was discovered in 1981 and characterized by the appearance symptoms including persistent lymphadenopathy and opportunistic infections such as Kaposi sarcoma, Pneumocystis carinii pneumonia. In addition, it was found that all of these patients shared a common defect in cell-mediated immunity characterized by a significant decrease in CD4+T lymphocytes, later revealed to be a principal target of infection [1-3]. Three years later, the causative agent of AIDS was identified as HIV [4, 5]. HIV was classified under the lentivirus genus and the Retroviridae family. It is an enveloped virus with a size of about 100 nm in diameter. Its genome consists of two identical copies of positive-sense single stranded RNA (ssRNA) that are reverse transcribed into cDNA in infected cells [2, 5]. Each ssRNA is about 9,500 nucleotides in length, and encodes three structural genes called gag, pol, env, and a complex of several other nonstructural regulatory genes known as tat, rev, nef, vif, vpr, and vpu [2, 5]. The gag gene encodes the viral structural proteins including p24 (capsid), p17 (matrix), p7 (nucleocapsid). The pol gene, on the other hand, encodes viral enzymes including p32 (integrase), p66 and p51 (reverse transcriptase), and p10 (protease). The env gene encodes the coat glycoproteins gp120 (surface) and gp41 (transmembrane), which play a major role in viral attachment and fusion with host target cell membranes. The nonstructural genes including transactivator of transcription (Tat), regulator of virion protein expression (Rev), negative regulatory factor (Nef), viral infectivity factor (Vif), viral protein R (Vpr), and viral protein U (Vpu) proteins, respectively, are also essential for viral replication and pathogenesis [2, 5].


3. The immune system and its cellular components

The immune system is a very complex and dynamic network, which can be broadly divided into innate and adaptive components [4,6,7]. The cellular components of innate immunity include dendritic cells, natural killer (NK) cells, NK T cells, macrophages, and granulocytes, whereas, the adaptive immunity is mediated by B and T lymphocytes [4,6-8]. The components of both branches act in conjunction and are regulated by soluble mediator proteins known as cytokines and chemokines in order to fight, clear, and protect the host from a wide variety of pathogens [4,6-8].

3.1. The innate immune system

The innate immune system is the first line of defense against invading pathogens. Viral infections including HIV induce the interferon (IFN) response that is characterized by the production and secretion of pro-inflammatory cytokines including type-I IFN (IFN-α/β). These cytokines have antimicrobial and anti-proliferative properties and serve to propagate the adaptive immune responses [9]. In humans, cellular RNA molecules are short stem secondary structures. In contrast, RNA viruses produce long dsRNA molecules in the infected cells as a part of their life cycle. Thus, the long dsRNA can be recognized as a foreign molecule and triggers both cellular and humoral innate immune responses [10]. There are two well characterized ways in which a cell can recognize pathogens. Distinct extracellular pathogen components are recognized by different Toll- like receptors (TLR) expressed on the cell surface or in the endosome such as TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 [11]. Intracellular replicating pathogens however, are recognized by RNA helicases, which are encoded by the retinoic acid-inducible gene I (RIG-I) and/or melanoma differentiation-associated gene 5 (MDA5) [12]. Following viral recognition, the activation and translocation of the transcription factor nuclear factor κB (NFκB) and interferon-regulatory factor (IRF)-3 to the nucleus occurs and promotes the transcription of IFN type I [13]. Production of type-I IFN stimulates the surrounding cells to produce a wide range of antiviral proteins including protein kinase R (PKR), myxovirus resistance factor, 2'-5' oligoadenylate synthase/RNaseL and dsRNA adenosine deaminase 1, which subsequently leads to the activation of eukaryotic initiation factor (eIF)-2, and translation inhibition of both host and viral mRNAs [14].

Monocytes, which are the precursors of macrophages, as a part of the innate immune system, play a major role in controlling and clearing pathogens. They exhibit antimicrobial, antifungal, and antiparasitic properties [4,6-8]. They possess phagocytic and endocytic activity. In addition, they act as antigen presenting cells by uptaking, processing, and presenting antigen in the context of major histocompatibility complex (MHC) class II to CD4+ T cells. Moreover, they secrete inflammatory cytokines such as IFN type-I (IFN-α/β), interleukin (IL)-1, IL-6, IL-12, and chemokines such as IL-8 [4,6-8]. This stimulates the adaptive immune system and leads to the activation and differentiation of B and T lymphocyte populations. These important monocyte/macrophage (M/M) functions are largely driven and regulated by the responsiveness of these cells to numerous cytokines such as IFN-γ, IL-10, and Tumor Necrosis Factor (TNF)-α, and signals delivered to them via the TLR family through recognition of different microbial products such as bacterial lipopolysaccharide (LPS) and viral proteins and nucleic acids including those of HIV [4,6-8].

3.2. The adaptive immune system

B and T lymphocytes form the arm of the adaptive and antigen-specific immune response. B lymphocytes are antigen presenting cells, upon antigenic and cytokine stimulation they differentiate into plasma cells which produce antigen-specific antibodies. While T lymphocytes are divided into two distinct populations: helper and cytotoxic cells which are differ in their function T helper lymphocytes express the CD4 surface receptor, recognize antigens presented as peptide epitopes bound to MHC class II molecules expressed on the surface of antigen presenting cells, and function mainly as cytokine producing cells to ‘help’ the development of the immune response. Activated CD4+ T cells differentiate into T helper (Th)-1 and Th-2 effectors, and memory cell sub-populations. The Th-1 and Th-2 subsets of CD4+ T cells were originally defined by their polarized cytokine production patterns [15,16]. Th-1 cells produce IFN-γ, IL-2, IL-12 and lymphotoxin-α, which enhance antigen presentation, phagocytosis, and cell-mediated cytotoxicity. On the other hand, Th-2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13, promoting more of an antibody response [16-18]. Cytotoxic T lymphocytes however, express the CD8 surface receptor, and recognize antigenic peptide epitopes presented on cell surface MHC class I molecules. Antigen-activated CD8+ T cells also proliferate and differentiate into effectors and memory cell populations, largely in response to cytokines that share the common γc receptor, such as IL-2, IL-15, and IL-7. Cytotoxic T cells secrete IFN-γ, which inhibits virus replication, as well as perforin, and granzymes in order to kill virus-infected cells.

3.3. HIV and the cellular immune response

HIV is commonly transmitted by sexual contact, and thus it initially interacts with and activates the innate immune system and antigen presenting cells including macrophages and dendritic cells at the mucosal surfaces [5,19,20]. Importantly, these cells then migrate to the lymphoid tissues and thereby also deliver the virus to other susceptible cells located at these sites. In the lymphoid tissues, HIV interacts and infects other cells such as CD4+ T cells and is able to disseminate to other areas such as the brain and gut [5,21]. Subsequently, inflammatory cells and cytokines accumulate during chronic infection and immune activation causing severe reactions and tissue pathology. This includes destruction of regulatory immune cells, mainly CD4+ T cells, and overall impairment of immune functions, which are the hallmarks of chronic HIV infection [5,22-24]. Studies have shown that M/M and T lymphocyte functions are impaired over the course of HIV infection, thus contributing to the overall immune dysfunction and appearance of the opportunistic infections observed in HIV-infected patients. Several ex vivo and in vitro studies have reported that many M/M defects arise during chronic HIV infection including poor phagocytic activity [25-27], altered cytokine and chemokine secretion [24,28-31], impaired antigen uptake and MHC class II molecule expression [32,33]. Other studies have shown defects in T lymphocyte effector functions including impairment of CD4 T lymphocytes to produce IL-2 and to proliferate in response to recall antigens (influenza, tetanus toxoid), alloantigens (mixed lymphocytes reaction), or exogenous mitogens (phytohemagglutinin) [34,35]. Also, CD8 T lymphocytes exhibit an altered differentiation and proliferative phenotype and impaired capacity to kill virus-infected cells and clear the virus [36]. However, the molecular mechanism by which HIV impairs these cellular functions remains unclear. One possible mechanism by which chronic HIV infection may adversely affect immune cell function is through the modulation of cell signaling molecules, as observed in several cell types including M/M, CD4+ and CD8+ T cells, and neuronal cells [37-42]. This may occur by the direct action of HIV and its different immunomodulatory proteins such as Gp120, Nef, Tat, and Vpr, or indirectly via its effects on the cytokine secretion profile induced during the course of the disease as discussed in more detail below [43-46].


4. Cytokines

As mentioned above, cytokines are small secreted proteins with molecular weights of about 10-40 kDa [18,47,48]. These proteins function as mediators to regulate both the innate and adaptive immune responses [4,6,7]. They transmit the biochemical message from the extracellular environment to the nucleus of the targeted cell via cytokine-cytokine receptor interaction and subsequent triggering of complex intracellular signal transduction [49,50]. They can affect cell function in a paracrine as well as an autocrine manner. There are many cytokines produced by the immune system. Certain cytokines are associated with the initial response to an infection or inflammation and are referred to as inflammatory cytokines. Other cytokines are induced according to the nature of the infectious agent and the type of immune responses produced against them. For instance, infection with Influenza virus, Vaccinia virus, or Listeria monocytogenes is known to induce a Th-1 immune response [51]. This type of immune response is associated with the production of cytokines such as IL-2, IFN-γ, and IL-12, which regulate cell-mediated immunity including delayed hypersensitivity reactions, activation of macrophages and leukocyte cytolytic processes, and result in the protection and elimination of intracellular pathogens [16,50,52]. On the other hand, infection with Nippostrongylus barsiliensis or Leishmania major is known to induce a Th-2 response [51]. This immune response is characterized by secretion of cytokines such as IL-4, IL-5, IL-9, IL-10, and IL-13 that predominantly regulate antibody-mediated immunity and generally lead to the protection and clearance of extracellular antigens/pathogens [16,50,52]. During chronic HIV infection, both types of immune response and their associated cytokines are dysregulated, which may result in altered M/M and lymphocyte functions and increased susceptibility to programmed cell death (PCD) [53-56].

The following section will focus on cytokines that play an important role in regulating M/M as well as T lymphocytes effector functions and cell survival. These cytokines include IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-10, IL-4, IL-2, IL-7, and IL-15 (summarized in Table 1).

Cytokine Producer cells Effects on M/M, T cells STAT signaling in viremic patient
IFN-γ Th1 lymphocytes, activated NK cells, and CD8 T cells Upregulates the activation of MHC class I and II, and activates pathogen killing. Increased STAT1 activation
IFN-α Leukocytes, and virus-infected cells Upregulates the activation of MHC class I. Decreased STAT1 activation
GM-CSF T cells, Macrophages Stimulates growth and differentiation of myelomonocytic lineage cells. Enhances phagocytosis. Not significantly
IL-10 T cells, Macrophages Potent suppressor of monocytes/macrophage function (e.g. inhibits MHC class II activation, antigen presentation, and phagocytosis). Not significantly
IL-4 Th2 lymphocytes Induces activation of MHC class II, induces endocytosis, and mannose receptor activation. Not significantly affected
IL-2 Activated T lymphocytes and dendritic cells Promotes T cell proliferation and T reg development Decreased STAT5 activation
IL-7 Bone marrow and stromal cells in lymphoid organs Maintains thymocytes survival. Decreased STAT5 activation
IL-15 M/M, dendritic cells, mast cells, epithelial cells, and fibroblast Induces survival and proliferation of CD8 T cells, NK cells and NK T cells. Not significantly affected

Table 1.

Cytokines and their effects on monocyte/macrophage and T lymphocyte functions

4.1. Cytokines that affect monocytes

Cytokines such as IFN-γ and GM-CSF affect mainly M/M, while, IL-10 and IL-4 act on both M/M and lymphocytes. IFN-γ is an 18-kDa potent pleiotropic cytokine produced by NK cells, NK T cells, Th-1, and CD8+ T cells. It has a critical role in the regulation of both innate and adaptive immunity [57,58]. It inhibits Th-2 and promotes Th-1 cell polarization and differentiation. Also, it inhibits viral replication and regulates cell death [57,58]. Moreover, it activates monocytes and macrophages, increases MHC class II expression, promotes antigen processing and presentation, and enhances their phagocytic, antimicrobial, and tumoricidal activities [59-64]. For instance, it has been shown that treatment of M/M with IFN-γ enhanced phagocytic activity against many pathogens including Aspergillus fumigatus, Cryptococcus neoformans, Listeria monocytogenes, Mycobacterium avium, Toxoplama cruzi and gondii [26,61,65]. Other studies have revealed that the lack of IFN-γ responses, such as in IFN- γ, IFN-γ receptor (IFN-γR), or STAT1-deficient mice, or in patients with mutations in the IFN-γ-R gene, lead to impaired immunity and increased susceptibility to infection [66-70]. GM-CSF is a 22-kDa protein secreted by macrophages and T cells. It facilitates growth and differentiation of monocyte and granulocyte lineages. It also enhances M/M effector functions including phagocytic, antimicrobial and antiparasitic activities [71,72].

IL-10 is a potent immunosuppressive and anti-inflammatory cytokine produced by macrophages and T cells. It downregulates MHC class II molecule expression and antigen presentation to CD4+ T cells [73,74]. It also inhibits the expression of co-stimulatory molecules, B7.1/B7.2, on monocytes and macrophages as well as the production of various cytokines such as TNF-α, IL-1, IL-2, IFN-γ, IL-3, and GM-CSF [73,75,76]. In addition, it suppresses macrophage nitric oxide production, and anti-fungal activity [77]. Moreover, it stimulates proliferation and differentiation of B cells, and polarizes T cells towards a Th-2 type response [17,78].

IL-4 is a 20-kDa cytokine secreted by Th-2 lymphocytes that promotes a Th-2 immune response. It has dual immunoregulatory functions [18]. It activates B cell differentiation and antibody production. Also, it enhances macrophage cytotoxicity and their expression of MHC class II and mannose receptor [79-84]. On the other hand, it inhibits cytokine secretion such as TNF-α, IL-1, IL-6, IL-18, GM-CSF and granulocyte colony-stimulating factor (G-CSF) [85-94]. It also suppresses cytokine-induced macrophage activation, oxidative burst, and intracellular killing [62,95]. Moreover, it downregulates monocyte adhesion and CD14 expression [96,97], monocyte-mediated cytotoxicity, nitric oxide production, and anti-fungal activity [77,98].

4.2. Cytokines that affect lymphocytes

Cytokines that share the γ-chain receptor, such as IL-2, IL-7, and IL-15, play a critical role in lymphocyte growth and differentiation [36,99]. IL-2 is a protein produced mainly by activated CD4 but also CD8 T lymphocytes and dendritic cells. It is a T cell growth factor and plays a critical role in regulating the immune response. It plays a major role in activating the immune system in the presence of antigenic stimulation, but also in downregulating this response following pathogen clearance. IL-2 stimulates T cell proliferation and is essential for developing regulatory T cells. In addition, IL-2 has been shown to upregulate expression of Tumor Necrosis Family death receptor ligand, FasL, in activated T cells thereby enhancing their susceptibility to activation-induced cell death [100,101].

IL-7 is a pleiotropic cytokine secreted by bone marrow and stromal cells of lymphoid organs. It stimulates the growth and maintains the survival of thymocytes (B and T lymphocyte progenitor cells) by increasing the expression of the anti-apoptotic molecule Bcl-2 and down-regulating the expression of the pro-apoptotic molecule Bax [102-105]. Thus, it is an essential element for T cell survival, proliferation, and optimal effector function.

IL-15 is a cytokine that is produced by different cell types including M/M, dendritic cells, mast cells, epithelial cells, and fibroblasts. It plays an important role in growth and homeostasis. It provokes adaptive and innate immune responses. For example, it shares several biological effects with IL-2 such as mediating survival and proliferation of naïve and memory CD8 T cells. It also stimulates NK T cell expansion and regulates the development of NK cells and its cytotoxicity [36,99,106].

It has been reported that during the course of chronic HIV infection, many inflammatory and anti-inflammatory cytokines such as TNF-α, IFN-β, IFN-γ, IL-18, IL-2, IL-10, and IL-4 are increased in patients serum [77,107-115], and thus may play a role in the alteration of M/M and T lymphocyte functions and signaling pathways (Table 1) [38-42]. Several studies have also proposed and used cytokines such as IFN-γ, GM-CSF, IL-4, IL-2, IL-7 and IL-15 as therapeutics in clinical trials for diseases including HIV and myeloma in an attempt to compensate for impairments in the cytokine network [36,99,116-118].

4.3. Cytokine signaling pathways

Cytokine signaling pathways can be defined as biochemical signaling cascades that are triggered within minutes to relay the information required to mediate various cytokine-dependent cellular functions [119-123]. Most cytokines share general mechanisms of signal transduction in which cytokine-cytokine receptor binding causes the assembly of the specific receptor subunits. Subsequently, a number of tyrosine kinases from the Src and Syk families are activated leading to signal transduction through mainly three major signaling pathways: (i) Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT), (ii) Phosphoinositide 3-kinase (PI3K), and (iii) Mitogen-activated protein kinase (MAPK) [124-126]. These signaling pathways form a very complex and evolutionarily conserved network.

A general overview of these cascades is illustrated in Figure 1. Briefly, when the ligand-receptor interaction occurs, subsequent events are activated based on the nature of these ligands and receptors. For example, a receptor with intrinsic kinase activity (e.g. epidermal growth factor receptor) is usually autophosphorylated directly leading to the creation of a docking site for an adapter protein complex called Grb2/SOS (son of sevenless) [36]. As a result, SOS is recruited to the plasma membrane where it encounters and activates a small G protein named Ras [36,127,128]. Activated Ras induces the activation of several downstream signaling molecules, including a serine/threonine kinase called Raf, which in turn activates the MAPK and PI3K signaling pathways [36,127,129]. PI3K signaling molecules can also be activated directly via the p110α catalytic subunit of the PI3K [127]. A receptor with no intrinsic kinase activity (e.g. cytokine receptors) generally requires activation of receptor-associated kinases such as JAKs for its phosphorylation. Subsequently, activated JAKs can activate the STAT signaling pathway directly and also interact with and activate Grb2/SOS, which in turn activates PI3K and MAPK signaling [36,122,130,131].

Figure 1.

Overview of the major intracellular signaling pathways Upon ligand-receptor binding, signal transduction triggers takes place based on the type and nature of the receptor. If the receptor has intrinsic tyrosine kinase activity, autophosphorylation of the tyrosine residues of the receptor will occur and thus creates docking sites for a variety of different signaling molecules that have SH2 and PTB domains. Grb2/SOS complexes bind to docking sites and lead to recruitment of SOS (son of sevenless) to the plasma membrane where they interact with Ras. Subsequently, activated Ras molecules activate several downstream molecules including Raf, MAPKK, and MAPK. The PI3K signaling pathway can be activated directly via the p110α catalytic subunit of the PI3K. Phosphorylated receptors also activate phospholipase Cγ (PLCγ), which activate Protein Kinase C (PKC) and calcium-dependent signaling pathways. If the receptor has no intrinsic kinase activity, activation of the Janus Kinase (Jak) or other receptor-associated kinase occurs. Subsequently, activated Jaks phosphorylate the receptor and thus create docking sites for various signaling molecules including members of the Signal Transducers and Activators of Transcription (STAT) family. Signal transduction culminates in the transcriptional activation of STAT responsive genes that influence cellular proliferation, differentiation, cytokine production, mobility, phagocytosis, and survival [modified from [187]].

Evidence has also demonstrated the presence of a complex crosstalk between these pathways. For instance, it has been shown that Jak2 is responsible for the activation of STAT, Erk MAPK, and Akt signaling pathways in response to growth hormone in hepatoma and preadipocyte cells [132]. Another report has demonstrated a role for Akt in serine phosphorylation of the STAT1 transcription factor and upregulation of gene expression in response to IFN-γ [133].

HIV-induced perturbation of the JAK/STAT, PI3K, and MAPK signaling pathways in immune cells including M/M and T lymphocytes has been documented (summarized in Table 1, 4) [41,134-146]. These effects appear to be to the advantage of the virus. On one hand, it may help the virus to replicate and establish infection. On the other hand, it may also help the virus to escape the immune system. In the following subsections, we will provide a brief overview of cytokine signaling and where HIV infection appears to target these cascades.

4.3.1. JAK/STAT signaling pathway

The JAK/STAT pathway is one of the major signaling pathways involved in cytokine responses. Studies have shown that many ligands such as epidermal growth factor (EGF), receptor tyrosine kinases (RTK), G protein-coupled receptors (GPCR) and several cytokine families including interferons and interleukins are the main triggers of the JAK/STAT signaling cascade [147-149]. An overview of the JAK/STAT signal transduction pathway is illustrated in Figure 1. Initially, cytokine-receptor interaction triggers tyrosine transphosphorylation of receptor-associated JAKs. This is followed by phosphorylation of receptor cytoplasmic domains by JAKs and recruitment of latent STAT proteins via their Src homology 2 (SH2) domains to the activated (tyrosine phosphorylated) receptor. This is followed by STAT tyrosine phosphorylation. Activated STATs form dimers via their SH2 domains and are translocated into the nucleus where they bind STAT responsive elements [119,120,123], and thus promote transcription of STAT responsive genes such as cytokine-inducible SH2-containing protein (CIS), members of the IRF family, and numerous other genes [150-153].

In mammalian cells, four JAKs (Jak1, Jak2, Jak3 and Tyk2) and seven STAT proteins (STAT1, 2, 3, 4, 5a, 5b, and 6) with their different isoforms have been identified. [147,154]. Through IL-6-induced signaling, Jak1 is the principal kinase in the downstream signaling cascade. It has been shown in many cell lines that down regulation of Jak1 would lead to impaired signal transduction. Activated JAKs lead to phosphorylation of STAT proteins. However, JAK kinases do not appear to show specificity for a particular STAT protein [147,154]. STAT proteins play an important role in regulating and maintaining both innate and adaptive immune responses (summarized in Table 2) [119-121,123]. For instance, studies have suggested that impairment of JAK/STAT signaling may increase susceptibility to many infections including HIV [65,67,70,155].

STAT gene Activating cytokines Examples of STAT responsive genes Phenotype of knockout mice
STAT1 IFNs,IL-6,IL-10 IRF-1, ISG54, MIG, GBP, CIITA Impaired IFN and innate immune responses, increase susceptibility to tumors, opportunistic and viral infections
STAT2 IFNs IRF-1, ISG54 Impaired Type-1 IFN responses
STAT3 IL-2,IL-6,IL-10 JunB, SAA3, JAB, C-reactive protein, Bcl-xL Embryonic lethal
STAT4 IL-12 IFN-γ, IRF-1, MHC class II, CD23, Fc-γRI Defect in IL-4 and IL-12 responses, and impaired Th1 differentiation.
STAT5 a, b Numerous (e.g. IL-2,IL-7,IL-15, GM-CSF) CIS, IL-2R-α, β-casein, osm, pim1, p21 Impaired proliferation, growth and survival, defect in IL-2 responses, impaired growth.
STAT6 IL-4,IL-13 IL-4R-α, C-γ-1, C-γ-4 Defect in IL-4 responses, and impaired Th1 differentiation.

Table 2.

STATs proteins and their role in the immune system

A number of reports have suggested that defects in cytokine responsiveness arise in different cell types during chronic HIV infection and these defects could be due to the direct effects of HIV and/or its proteins, or due to indirect effects associated with alterations of the host cytokine profile [38-42,139,141-143,156]. In M/M, it has been revealed that GM-CSF-induced STAT5 activation in monocyte-derived macrophages (MDM) is inhibited by in vitro HIV-1 infection [156]. Other in vitro reports have suggested that HIV and its Gp120 and Nef proteins are capable of activating STAT1 and STAT3 in monocytic cell lines and MDM [141-143]. Recently, the HIV matrix protein p17 has been shown to induce STAT1 and pro-inflammatory cytokines in macrophages [139]. Moreover, in ex vivo studies, we found that among the responses to cytokines tested (IFN-γ, IFN-α, IL-10, IL-4, and GM-CSF) in terms of STAT induction in monocytes, only IFN-γ showed a significant upregulation of STAT1 activation in HIV+ patients that were off antiretroviral therapy (ART) compared to HIV- controls and patients on ART [39]. Furthermore, this potentiation of IFN-γ-induced STAT1 activation was associated with increased total STAT1 expression levels and monocyte cell death [39]. Another ex vivo study has shown a defect in IFN-α induced STAT1 activation in monocytes obtained from a similar set of HIV patients, and this defect was due to the decreased IFN-α receptor expression levels on these cells [42].

In lymphocytes, we and others have shown that both IL-7Rα expression and IL-7-induced STAT5 activation was impaired in CD8 T cells from HIV+ patients [36,40,41]. STAT activation in response to IL-4 and IL-10 did not appear to be similarly impaired [40]. We also found that IL-2-induced STAT5 activation was inhibited in CD8+ T cells from a subset of HIV-infected patients naive to therapy, but was restored, at least in part, after ART [38]. Somewhat similar results have been observed in other in vitro studies in which activation of STAT5 in response to IL-2 was inhibited by HIV-1 infection through prior Gp120-CD4 interactions in CD4+ T cells [37,144].

4.3.2. PI3K signaling pathway

Phosphoinositide 3-kinases or phosphatidylinositol-3-kinases (PI3Ks) belong to a family of enzymes that have serine/threonine kinase activity. These enzymes can be activated by various stimuli including growth factors, antigens, cytokines [157,158], and are capable of phosphorylating the third position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns) [157,159]. This family is composed of four classes, which differ in their structure and functions (known as Ia, Ib, II, and III). However, all of them contain at least one catalytic domain and one regulatory domain [157,159]. Many PI3K cellular functions rely on the ability of PI3Ks to activate protein kinase B (PKB, also known as Akt) (Figure 1). In humans, three Akt genes have been identified named akt1, akt2, and akt3.

PI3-kinases have been shown to play a major role in diverse cellular functions, including cell growth, proliferation, differentiation, survival, and migration [160-163]. Thus, dysregulation of this pathway may influence different cellular responses that are associated with immunity as well as carcinogenesis (Table 3) [157,164]. It has also been reported that there is a basal activation of the PI3K/Akt pathways in macrophages that is required for their survival [165]. Certain reports have suggested a critical role for PI3K signaling in chronic immune activation by promoting cell survival [166]. For instance, an in vitro study has revealed that HIV infection and its protein Tat was sufficient to activate the PI3K/Akt pathway in macrophages [166]. Interestingly, PI3K/Akt inhibitors including Miltefosine, an antiprotozoal drug known to inhibit PI3K/Akt pathway, significantly reduced HIV-1 production from infected macrophages and increased susceptibility to cell death in response to extracellular stress, as compared to uninfected cells [166]. Another study has shown that inhibition of Akt phosphorylation is required for TNF related apoptosis inducing ligand (TRAIL)-induced cell death in HIV infected macrophages [167].

Target Gene Phenotype
p85α Decreased B cell development and activation, increased antiviral responses
p85β Increased insulin sensitivity
p110α Embryonic lethal and defective proliferation
P110β Embryonic lethal
P110γ Decreased T cell development and activation, decreased inflammation, chemotaxis, and oxidative burst
PTEN Embryonic lethal, autoimmune disease, decreased T cell development, increased T cell activation, and chemotaxis
SHIP1 Increased myeloid cell proliferation and survival, increased B cell activation, chemotaxis, and mast cell degranulation
SHIP2 Perinatal lethal

Table 3.

Characteristics of PI3K knockout mice

Viral protein Effects on M/M Effects on lymphocytes
gp120 Stimulates STAT1 activation Stimulates STAT1 activation
p17 Stimulates STAT1 activation No report
Tat Stimulates MAPK, Akt activation Stimulates Akt, MAPK activation
Nef Stimulates STAT1 & 3, MAPK activation Stimulates Erk & p38 MAPK activation
Vpr Stimulates MAPK activation No report
HIV infection
Inhibits STAT5 activation, Stimulates STAT1, Akt activation Inhibits STAT5 activation, Stimulates STAT1, MAPK activation

Table 4.

HIV viral proteins and their effects on monocytes/macrophages and lymphocytes

4.3.3. MAPK signaling pathway

Mitogen-activated protein kinases (MAPKs) are also a family of enzymes that have serine/threonine kinase activity [168]. This family of kinases is generally activated in response to various extracellular stimuli such as growth factors and inflammatory signals, as well as cellular stress. They regulate different cellular processes including mitosis, proliferation, differentiation, and cell death [168]. The MAPK family is composed of three major subfamilies of kinases known as the extracellular receptor kinases (ERKs), the c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) and the p38 MAP kinases [169]. Activation of a specific MAP kinase requires activation of a small GTP binding protein (e.g. Ras) which results in the phosphorylation of a series of downstream kinases (Figure 1) [128]. Activation of the MAPK kinase kinase (MAPKKK) (e.g. Raf) leads to the activation of downstream MAPK kinase (MAPKK), and finally, specific MAPK (p38, Erk or JNK) [170,171]. The Erk MAPK family is found in two isoforms called Erk1 and Erk2. Both isoforms are phosphorylated by members of the MEK family, which are often activated by extracellular stimuli such as growth factors, LPS and chemotherapeutic agents [129,172,173]. The JNK family is found in three isoforms named JNK1, JNK2, and JNK3 [174], while the P38 family is found in five different isoforms called p38 (SAPK2), p38β, p38β2, p38γ (SAPK3), and p38δ [175,176]. Both JNK and p38 MAPKs are phosphorylated by SAPK/Erk kinases (SEKs) and mitogen-activated protein kinase kinases (MKKs), which are usually induced by inflammatory cytokines as well as other stressors such as endotoxins, reactive oxygen species, protein synthesis inhibitors, and ultraviolet (UV) irradiation [174,177-179]. MAPKs have been shown to activate various downstream transcription factors such as activator transcription factor (ATF)-2, SP-1 (a member of Specificity Protein/Krüppel-like Factor family) and activator protein (AP)-1, and even STAT3 [178,180-182].

Several reports have shown that activation of the MAPKs resulted in phosphorylation of HIV Rev, Tat, Nef, and p17 proteins and enhanced viral replication [140,183]. Other studies have demonstrated a role for MAPK in regulating monocyte and lymphocyte functions and cell death during HIV infection. For example, in monocytes, it has been shown that the HIV Tat protein stimulates IL-10 production via activation of calcium/MAPK signaling pathways in human monocytes [134,135,184]. Another report has suggested that HIV Vpr is capable of inducing programmed cell death in primary monocytes and the monocytic cell line THP-1 cells [185]. Further, it has been shown that HIV and its protein nef induced FasL, Programmed Death-1 expression and apoptosis in peripheral blood mononuclear cells (PBMCs) and the Jurkat T cell line through activation of the p38 MAPK signaling pathway [138,186].

Figure 2.

A model for the effect of chronic HIV infection on cellular signal transduction Cell signaling molecules may be regulated directly or indirectly during chronic HIV infection. In the direct setting, HIV and its proteins (Gp120, Nef, Tat, Vpr), through the binding of cellular receptors or internalization by endocytosis, alter signaling pathways including JAK/STAT, PI3K, and MAPK. In the indirect scenario, HIV infection may adversely affects the host cytokine network, which may in turn affect signal transduction. Both scenarios may thus promote viral replication and defective host immune effector functions and reduce immune cell survival [modified from [187].


5. Conclusion

It is well established that HIV targets the immune system and mainly immune cells that express the CD4 surface receptor, but the virus is not exclusive to these cells. Thus, through the course of chronic HIV infection the immune system becomes progressively impaired and unable to protect the body from opportunistic pathogens. This impairment not only includes CD4 T cell depletion, but also the dysregulation of immune cell effector functions, and a skewed cytokine/chemokine expression profile. These effects may be due to the disruption of the described signaling pathways as a result of direct HIV infection, through the action of numerous viral proteins and/or the chronic, but defective state of host immune activation, as summarized in Figure 2. Understanding the molecular mechanisms and identifying the key molecules involved in this impairment may provide important insight towards developing new therapeutic strategies aimed at prolonging the life span of HIV infected individuals and clearing HIV from the host.


  1. 1. Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983 May 20;220(4599):868-71.
  2. 2. Chinen J, Shearer WT. Molecular virology and immunology of HIV infection. J Allergy Clin Immunol 2002 Aug;110(2):189-98.
  3. 3. Levy JA, Hoffman AD, Kramer SM, Landis JA, Shimabukuro JM, Oshiro LS. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science 1984 Aug 24;225(4664):840-2.
  4. 4. Chaplin DD. 1. Overview of the immune response. J Allergy Clin Immunol 2003 Feb;111(2 Suppl):S442-S459.
  5. 5. Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 1993 Mar;57(1):183-289.
  6. 6. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med 2000 Jul 13;343(2):108-17.
  7. 7. Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med 2000 Jul 6;343(1):37-49.
  8. 8. Medzhitov R, Janeway C, Jr. Innate immunity. N Engl J Med 2000 Aug 3;343(5):338-44.
  9. 9. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 2005;23:275-306.
  10. 10. Cullen BR. Is RNA interference involved in intrinsic antiviral immunity in mammals? Nat Immunol 2006 Jun;7(6):563-7.
  11. 11. Uematsu S, Akira S. The role of Toll-like receptors in immune disorders. Expert Opin Biol Ther 2006 Mar;6(3):203-14.
  12. 12. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006 May 4;441(7089):101-5.
  13. 13. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 2005 Mar;11(3):263-70.
  14. 14. Schlee M, Hornung V, Hartmann G. siRNA and isRNA: two edges of one sword. Mol Ther 2006 Oct;14(4):463-70.
  15. 15. Romagnani S. Regulation of the T cell response. Clin Exp Allergy 2006 Nov;36(11):1357-66.
  16. 16. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145-73.
  17. 17. Itoh K, Hirohata S. The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 1995 May 1;154(9):4341-50.
  18. 18. Paul WE. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 1991 May 1;77(9):1859-70.
  19. 19. de Jong MA, Geijtenbeek TB. Human immunodeficiency virus-1 acquisition in genital mucosa: Langerhans cells as key-players. J Intern Med 2009 Jan;265(1):18-28.
  20. 20. Iqbal SM, Kaul R. Mucosal innate immunity as a determinant of HIV susceptibility. Am J Reprod Immunol 2008 Jan;59(1):44-54.
  21. 21. Sharma D, Bhattacharya J. Cellular & molecular basis of HIV-associated neuropathogenesis. Indian J Med Res 2009 Jun;129(6):637-51.
  22. 22. Boasso A, Shearer GM. Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol 2008 Mar;126(3):235-42.
  23. 23. Cadogan M, Dalgleish AG. HIV immunopathogenesis and strategies for intervention. Lancet Infect Dis 2008 Nov;8(11):675-84.
  24. 24. Yoo J, Chen H, Kraus T, Hirsch D, Polyak S, George I, et al. Altered cytokine production and accessory cell function after HIV-1 infection. J Immunol 1996 Aug 1;157(3):1313-20.
  25. 25. Baqui AA, Meiller TF, Zhang M, Falkler WA, Jr. The effects of HIV viral load on the phagocytic activity of monocytes activated with lipopolysaccharide from oral microorganisms. Immunopharmacol Immunotoxicol 1999 Aug;21(3):421-38.
  26. 26. Kedzierska K, Azzam R, Ellery P, Mak J, Jaworowski A, Crowe SM. Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. J Clin Virol 2003 Feb;26(2):247-63.
  27. 27. Thomas CA, Weinberger OK, Ziegler BL, Greenberg S, Schieren I, Silverstein SC, et al. Human immunodeficiency virus-1 env impairs Fc receptor-mediated phagocytosis via a cyclic adenosine monophosphate-dependent mechanism. Blood 1997 Nov 1;90(9):3760-5.
  28. 28. Amirayan-Chevillard N, Tissot-Dupont H, Capo C, Brunet C, Dignat-George F, Obadia Y, et al. Impact of highly active anti-retroviral therapy (HAART) on cytokine production and monocyte subsets in HIV-infected patients. Clin Exp Immunol 2000 Apr;120(1):107-12.
  29. 29. Choe W, Volsky DJ, Potash MJ. Induction of rapid and extensive beta-chemokine synthesis in macrophages by human immunodeficiency virus type 1 and gp120, independently of their coreceptor phenotype. J Virol 2001 Nov;75(22):10738-45.
  30. 30. Denis M, Ghadirian E. Alveolar macrophages from subjects infected with HIV-1 express macrophage inflammatory protein-1 alpha (MIP-1 alpha): contribution to the CD8+ alveolitis. Clin Exp Immunol 1994 May;96(2):187-92.
  31. 31. Tartakovsky B, Turner D, Vardinon N, Burke M, Yust I. Increased intracellular accumulation of macrophage inflammatory protein 1beta and its decreased secretion correlate with advanced HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol 1999 Apr 15;20(5):420-2.
  32. 32. Polyak S, Chen H, Hirsch D, George I, Hershberg R, Sperber K. Impaired class II expression and antigen uptake in monocytic cells after HIV-1 infection. J Immunol 1997 Sep 1;159(5):2177-88.
  33. 33. Shao L, Sperber K. Impaired regulation of HLA-DR expression in human immunodeficiency virus-infected monocytes. Clin Diagn Lab Immunol 2002 Jul;9(4):739-46.
  34. 34. Clerici M, Hakim FT, Venzon DJ, Blatt S, Hendrix CW, Wynn TA, et al. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest 1993 Mar;91(3):759-65.
  35. 35. Clerici M, Shearer GM. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993 Mar;14(3):107-11.
  36. 36. Sirskyj D, Theze J, Kumar A, Kryworuchko M. Disruption of the gamma c cytokine network in T cells during HIV infection. Cytokine 2008 Jul;43(1):1-14.
  37. 37. Kryworuchko M, Pasquier V, Theze J. Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes. Clin Exp Immunol 2003 Mar;131(3):422-7.
  38. 38. Kryworuchko M, Pasquier V, Keller H, David D, Goujard C, Gilquin J, et al. Defective interleukin-2-dependent STAT5 signalling in CD8 T lymphocytes from HIV-positive patients: restoration by antiretroviral therapy. AIDS 2004 Feb 20;18(3):421-6.
  39. 39. Alhetheel A, Yakubtsov Y, Abdkader K, Sant N, az-Mitoma F, Kumar A, et al. Amplification of the signal transducer and activator of transcription I signaling pathway and its association with apoptosis in monocytes from HIV-infected patients. AIDS 2008 Jun 19;22(10):1137-44.
  40. 40. Benoit A, Abdkader K, Sirskyj D, Alhetheel A, Sant N, az-Mitoma F, et al. Inverse association of repressor growth factor independent-1 with CD8 T cell interleukin (IL)-7 receptor [alpha] expression and limited signal transducers and activators of transcription signaling in response to IL-7 among [gamma]-chain cytokines in HIV patients. AIDS 2009 Jul 17;23(11):1341-7.
  41. 41. Vranjkovic A, Crawley AM, Patey A, Angel JB. IL-7-dependent STAT-5 activation and CD8+ T cell proliferation are impaired in HIV infection. J Leukoc Biol 2011 Apr;89(4):499-506.
  42. 42. Hardy GA, Sieg SF, Rodriguez B, Jiang W, Asaad R, Lederman MM, et al. Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression. Blood 2009 May 28;113(22):5497-505.
  43. 43. Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995 Jun 8;375(6531):497-500.
  44. 44. Yang Y, Tikhonov I, Ruckwardt TJ, Djavani M, Zapata JC, Pauza CD, et al. Monocytes treated with human immunodeficiency virus Tat kill uninfected CD4(+) cells by a tumor necrosis factor-related apoptosis-induced ligand-mediated mechanism. J Virol 2003 Jun;77(12):6700-8.
  45. 45. Zhang M, Li X, Pang X, Ding L, Wood O, Clouse K, et al. Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: upregulation of trail in primary human macrophages by HIV-1 tat. J Biomed Sci 2001 May;8(3):290-6.
  46. 46. Zhou D, Spector SA. Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS 2008 Mar 30;22(6):695-9.
  47. 47. Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol 2009 Jan;130(1):41-50.
  48. 48. Nadeen Ikram, Khalid Hassan, Samina Tufail. Cytokines. Int J Pathology 2004;2(1):47-58.
  49. 49. Aman MJ, Leonard WJ. Cytokine signaling: cytokine-inducible signaling inhibitors. Curr Biol 1997 Dec 1;7(12):R784-R788.
  50. 50. Cohen MC, Cohen S. Cytokine function: a study in biologic diversity. Am J Clin Pathol 1996 May;105(5):589-98.
  51. 51. Mueller SN, Hosiawa-Meagher KA, Konieczny BT, Sullivan BM, Bachmann MF, Locksley RM, et al. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science 2007 Aug 3;317(5838):670-4.
  52. 52. Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev 1996 Oct;9(4):532-62.
  53. 53. Alfano M, Poli G. The cytokine network in HIV infection. Curr Mol Med 2002 Dec;2(8):677-89.
  54. 54. Clerici M, Sarin A, Coffman RL, Wynn TA, Blatt SP, Hendrix CW, et al. Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis. Proc Natl Acad Sci U S A 1994 Dec 6;91(25):11811-5.
  55. 55. Estaquier J, Ameisen JC. A role for T-helper type-1 and type-2 cytokines in the regulation of human monocyte apoptosis. Blood 1997 Aug 15;90(4):1618-25.
  56. 56. Sinicco A, Biglino A, Sciandra M, Forno B, Pollono AM, Raiteri R, et al. Cytokine network and acute primary HIV-1 infection. AIDS 1993 Sep;7(9):1167-72.
  57. 57. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004 Feb;75(2):163-89.
  58. 58. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998;67:227-64.
  59. 59. Barrionuevo P, Beigier-Bompadre M, De La BS, Alves-Rosa MF, Fernandez G, Palermo MS, et al. Immune complexes (IC) down-regulate the basal and interferon-gamma-induced expression of MHC class II on human monocytes. Clin Exp Immunol 2001 Aug;125(2):251-7.
  60. 60. Dellacasagrande J, Ghigo E, Raoult D, Capo C, Mege JL. IFN-gamma-induced apoptosis and microbicidal activity in monocytes harboring the intracellular bacterium Coxiella burnetii require membrane TNF and homotypic cell adherence. J Immunol 2002 Dec 1;169(11):6309-15.
  61. 61. Kedzierska K, Paukovics G, Handley A, Hewish M, Hocking J, Cameron PU, et al. Interferon-gamma therapy activates human monocytes for enhanced phagocytosis of Mycobacterium avium complex in HIV-infected individuals. HIV Clin Trials 2004 Mar;5(2):80-5.
  62. 62. Lehn M, Weiser WY, Engelhorn S, Gillis S, Remold HG. IL-4 inhibits H2O2 production and antileishmanial capacity of human cultured monocytes mediated by IFN-gamma. J Immunol 1989 Nov 1;143(9):3020-4.
  63. 63. Griffith TS, Wiley SR, Kubin MZ, Sedger LM, Maliszewski CR, Fanger NA. Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL. J Exp Med 1999 Apr 19;189(8):1343-54.
  64. 64. Harris J, De Haro SA, Master SS, Keane J, Roberts EA, Delgado M, et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 2007 Sep;27(3):505-17.
  65. 65. Gavrilescu LC, Butcher BA, Del Rio L, Taylor GA, Denkers EY. STAT1 is essential for antimicrobial effector function but dispensable for gamma interferon production during Toxoplasma gondii infection. Infect Immun 2004 Mar;72(3):1257-64.
  66. 66. Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 1993 Mar 19;259(5102):1739-42.
  67. 67. Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 1996 Feb 9;84(3):443-50.
  68. 68. Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, et al. Immune response in mice that lack the interferon-gamma receptor. Science 1993 Mar 19;259(5102):1742-5.
  69. 69. Jouanguy E, Altare F, Lamhamedi-Cherradi S, Casanova JL. Infections in IFNGR-1-deficient children. J Interferon Cytokine Res 1997 Oct;17(10):583-7.
  70. 70. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 1996 Feb 9;84(3):431-42.
  71. 71. Armitage JO. Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1998 Dec 15;92(12):4491-508.
  72. 72. Hamilton JA, Anderson GP. GM-CSF Biology. Growth Factors 2004 Dec;22(4):225-31.
  73. 73. Moore KW, O'Garra A, de Waal MR, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol 1993;11:165-90.
  74. 74. Moore KW, de Waal MR, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683-765.
  75. 75. Akdis CA, Blaser K. Mechanisms of interleukin-10-mediated immune suppression. Immunology 2001 Jun;103(2):131-6.
  76. 76. Redpath S, Ghazal P, Gascoigne NR. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol 2001 Feb;9(2):86-92.
  77. 77. Cenci E, Romani L, Mencacci A, Spaccapelo R, Schiaffella E, Puccetti P, et al. Interleukin-4 and interleukin-10 inhibit nitric oxide-dependent macrophage killing of Candida albicans. Eur J Immunol 1993 May;23(5):1034-8.
  78. 78. Levy Y, Brouet JC. Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest 1994 Jan;93(1):424-8.
  79. 79. Crawford RM, Finbloom DS, Ohara J, Paul WE, Meltzer MS. B cell stimulatory factor-1 (interleukin 4) activates macrophages for increased tumoricidal activity and expression of Ia antigens. J Immunol 1987 Jul 1;139(1):135-41.
  80. 80. Littman BH, Dastvan FF, Carlson PL, Sanders KM. Regulation of monocyte/macrophage C2 production and HLA-DR expression by IL-4 (BSF-1) and IFN-gamma. J Immunol 1989 Jan 15;142(2):520-5.
  81. 81. Raveh D, Kruskal BA, Farland J, Ezekowitz RA. Th1 and Th2 cytokines cooperate to stimulate mannose-receptor-mediated phagocytosis. J Leukoc Biol 1998 Jul;64(1):108-13.
  82. 82. Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 1992 Jul 1;176(1):287-92.
  83. 83. te Velde AA, Klomp JP, Yard BA, de Vries JE, Figdor CG. Modulation of phenotypic and functional properties of human peripheral blood monocytes by IL-4. J Immunol 1988 Mar 1;140(5):1548-54.
  84. 84. Vercelli D, Jabara HH, Lee BW, Woodland N, Geha RS, Leung DY. Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes. J Exp Med 1988 Apr 1;167(4):1406-16.
  85. 85. Cheung DL, Hart PH, Vitti GF, Whitty GA, Hamilton JA. Contrasting effects of interferon-gamma and interleukin-4 on the interleukin-6 activity of stimulated human monocytes. Immunology 1990 Sep;71(1):70-5.
  86. 86. Donnelly RP, Fenton MJ, Kaufman JD, Gerrard TL. IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J Immunol 1991 May 15;146(10):3431-6.
  87. 87. Hamilton JA, Whitty GA, Royston AK, Cebon J, Layton JE. Interleukin-4 suppresses granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in stimulated human monocytes. Immunology 1992 Aug;76(4):566-71.
  88. 88. Hart PH, Jones CA, Finlay-Jones JJ. Interleukin-4 suppression of monocyte tumour necrosis factor-alpha production. Dependence on protein synthesis but not on cyclic AMP production. Immunology 1992 Aug;76(4):560-5.
  89. 89. Lee JD, Swisher SG, Minehart EH, McBride WH, Economou JS. Interleukin-4 downregulates interleukin-6 production in human peripheral blood mononuclear cells. J Leukoc Biol 1990 May;47(5):475-9.
  90. 90. Standiford TJ, Strieter RM, Chensue SW, Westwick J, Kasahara K, Kunkel SL. IL-4 inhibits the expression of IL-8 from stimulated human monocytes. J Immunol 1990 Sep 1;145(5):1435-9.
  91. 91. te Velde AA, Huijbens RJ, Heije K, de Vries JE, Figdor CG. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood 1990 Oct 1;76(7):1392-7.
  92. 92. Weiss L, Haeffner-Cavaillon N, Laude M, Cavaillon JM, Kazatchkine MD. Human T cells and interleukin 4 inhibit the release of interleukin 1 induced by lipopolysaccharide in serum-free cultures of autologous monocytes. Eur J Immunol 1989 Jul;19(7):1347-50.
  93. 93. Wong HL, Lotze MT, Wahl LM, Wahl SM. Administration of recombinant IL-4 to humans regulates gene expression, phenotype, and function in circulating monocytes. J Immunol 1992 Apr 1;148(7):2118-25.
  94. 94. Yanagawa H, Sone S, Sugihara K, Tanaka K, Ogura T. Interleukin-4 downregulates interleukin-6 production by human alveolar macrophages at protein and mRNA levels. Microbiol Immunol 1991;35(10):879-93.
  95. 95. Ho JL, He SH, Rios MJ, Wick EA. Interleukin-4 inhibits human macrophage activation by tumor necrosis factor, granulocyte-monocyte colony-stimulating factor, and interleukin-3 for antileishmanial activity and oxidative burst capacity. J Infect Dis 1992 Feb;165(2):344-51.
  96. 96. Elliott MJ, Gamble JR, Park LS, Vadas MA, Lopez AF. Inhibition of human monocyte adhesion by interleukin-4. Blood 1991 Jun 15;77(12):2739-45.
  97. 97. Lauener RP, Goyert SM, Geha RS, Vercelli D. Interleukin 4 down-regulates the expression of CD14 in normal human monocytes. Eur J Immunol 1990 Nov;20(11):2375-81.
  98. 98. Hudson MM, Markowitz AB, Gutterman JU, Knowles RD, Snyder JS, Kleinerman ES. Effect of recombinant human interleukin 4 on human monocyte activity. Cancer Res 1990 Jun 1;50(11):3154-8.
  99. 99. Leone A, Picker LJ, Sodora DL. IL-2, IL-7 and IL-15 as immuno-modulators during SIV/HIV vaccination and treatment. Curr HIV Res 2009 Jan;7(1):83-90.
  100. 100. Refaeli Y, Van PL, London CA, Tschopp J, Abbas AK. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 1998 May;8(5):615-23.
  101. 101. Van PL, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 1998 Apr 10;280(5361):243-8.
  102. 102. Durum SK, Candeias S, Nakajima H, Leonard WJ, Baird AM, Berg LJ, et al. Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: role of receptor-associated chains and locus accessibility. J Exp Med 1998 Dec 21;188(12):2233-41.
  103. 103. Hare KJ, Jenkinson EJ, Anderson G. An essential role for the IL-7 receptor during intrathymic expansion of the positively selected neonatal T cell repertoire. J Immunol 2000 Sep 1;165(5):2410-4.
  104. 104. Huang J, Muegge K. Control of chromatin accessibility for V(D)J recombination by interleukin-7. J Leukoc Biol 2001 Jun;69(6):907-11.
  105. 105. Kang J, DiBenedetto B, Narayan K, Zhao H, Der SD, Chambers CA. STAT5 is required for thymopoiesis in a development stage-specific manner. J Immunol 2004 Aug 15;173(4):2307-14.
  106. 106. Diallo M, Zheng Y, Chen X, He Y, Zhou H, Chen Z. Prospect of IL-2, IL-7, IL-15 and IL-21 for HIV immune-based therapy. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2011 Nov;36(11):1037-45.
  107. 107. Ameglio F, Cordiali FP, Solmone M, Bonifati C, Prignano G, Giglio A, et al. Serum IL-10 levels in HIV-positive subjects: correlation with CDC stages. J Biol Regul Homeost Agents 1994 Apr;8(2):48-52.
  108. 108. Minagawa T, Mizuno K, Hirano S, Asano M, Numata A, Kohanawa M, et al. Detection of high levels of immunoreactive human beta-1 interferon in sera from HIV-infected patients. Life Sci 1989;45(11):iii-vii.
  109. 109. Orsilles MA, Pieri E, Cooke P, Caula C. IL-2 and IL-10 serum levels in HIV-1-infected patients with or without active antiretroviral therapy. APMIS 2006 Jan;114(1):55-60.
  110. 110. Pugliese A, Torre D, Saini A, Pagliano G, Gallo G, Pistono PG, et al. Cytokine detection in HIV-1/HHV-8 co-infected subjects. Cell Biochem Funct 2002 Sep;20(3):191-4.
  111. 111. Reddy MM, Sorrell SJ, Lange M, Grieco MH. Tumor necrosis factor and HIV P24 antigen levels in serum of HIV-infected populations. J Acquir Immune Defic Syndr 1988;1(5):436-40.
  112. 112. Sato A, Tsuji K, Yamamura M, Morita Y, Kanzaki H, Tada J, et al. Increased type 2 cytokine expression by both CD4+ CD45RO+ T cells and CD8+ CD45RO+ T cells in blood circulation is associated with high serum IgE but not with atopic dermatitis. J Invest Dermatol 1998 Dec;111(6):1079-84.
  113. 113. Sindhu S, Toma E, Cordeiro P, Ahmad R, Morisset R, Menezes J. Relationship of in vivo and ex vivo levels of TH1 and TH2 cytokines with viremia in HAART patients with and without opportunistic infections. J Med Virol 2006 Apr;78(4):431-9.
  114. 114. Srikanth P, Castillo RC, Sridharan G, John TJ, Zachariah A, Mathai D, et al. Increase in plasma IL-10 levels and rapid loss of CD4+ T cells among HIV-infected individuals in south India. Int J STD AIDS 2000 Jan;11(1):49-51.
  115. 115. Stylianou E, Aukrust P, Kvale D, Muller F, Froland SS. IL-10 in HIV infection: increasing serum IL-10 levels with disease progression--down-regulatory effect of potent anti-retroviral therapy. Clin Exp Immunol 1999 Apr;116(1):115-20.
  116. 116. de GM, Castrillo JM, Fernandez Guerrero ML. Visceral leishmaniasis in patients with AIDS: report of three cases treated with pentavalent antimony and interferon-gamma. Clin Infect Dis 1993 Jul;17(1):56-8.
  117. 117. Squires KE, Brown ST, Armstrong D, Murphy WF, Murray HW. Interferon-gamma treatment for Mycobacterium avium-intracellular complex bacillemia in patients with AIDS. J Infect Dis 1992 Sep;166(3):686-7.
  118. 118. Sabbatini F, Bandera A, Ferrario G, Trabattoni D, Marchetti G, Franzetti F, et al. Qualitative immune modulation by interleukin-2 (IL-2) adjuvant therapy in immunological non responder HIV-infected patients. PLoS One 2010;5(11):e14119.
  119. 119. Ihle JN. The Stat family in cytokine signaling. Curr Opin Cell Biol 2001 Apr;13(2):211-7.
  120. 120. Imada K, Leonard WJ. The Jak-STAT pathway. Mol Immunol 2000 Jan;37(1-2):1-11.
  121. 121. Levy DE, Darnell JE, Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002 Sep;3(9):651-62.
  122. 122. O'Shea JJ. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 1997 Jul;7(1):1-11.
  123. 123. Ward AC, Touw I, Yoshimura A. The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 2000 Jan 1;95(1):19-29.
  124. 124. Pokrovskaja K, Panaretakis T, Grander D. Alternative signaling pathways regulating type I interferon-induced apoptosis. J Interferon Cytokine Res 2005 Dec;25(12):799-810.
  125. 125. Rani MR, Ransohoff RM. Alternative and accessory pathways in the regulation of IFN-beta-mediated gene expression. J Interferon Cytokine Res 2005 Dec;25(12):788-98.
  126. 126. Wong CK, Zhang J, Ip WK, Lam CW. Intracellular signal transduction in eosinophils and its clinical significance. Immunopharmacol Immunotoxicol 2002 May;24(2):165-86.
  127. 127. Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000 Oct 15;351 Pt 2:289-305.
  128. 128. Scita G, Tenca P, Frittoli E, Tocchetti A, Innocenti M, Giardina G, et al. Signaling from Ras to Rac and beyond: not just a matter of GEFs. EMBO J 2000 Jun 1;19(11):2393-8.
  129. 129. Caunt CJ, Finch AR, Sedgley KR, McArdle CA. Seven-transmembrane receptor signalling and ERK compartmentalization. Trends Endocrinol Metab 2006 Sep;17(7):276-83.
  130. 130. Darnell JE, Jr., Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994 Jun 3;264(5164):1415-21.
  131. 131. Stepkowski SM, Kirken RA. Janus tyrosine kinases and signal transducers and activators of transcription regulate critical functions of T cells in allograft rejection and transplantation tolerance. Transplantation 2006 Aug 15;82(3):295-303.
  132. 132. Jin H, Lanning NJ, Carter-Su C. JAK2, but not Src family kinases, is required for STAT, ERK, and Akt signaling in response to growth hormone in preadipocytes and hepatoma cells. Mol Endocrinol 2008 Aug;22(8):1825-41.
  133. 133. Nguyen H, Ramana CV, Bayes J, Stark GR. Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. J Biol Chem 2001 Sep 7;276(36):33361-8.
  134. 134. Gee K, Angel JB, Ma W, Mishra S, Gajanayaka N, Parato K, et al. Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells. J Biol Chem 2006 Oct 20;281(42):31647-58.
  135. 135. Leghmari K, Bennasser Y, Tkaczuk J, Bahraoui E. HIV-1 Tat protein induces IL-10 production by an alternative TNF-alpha-independent pathway in monocytes: role of PKC-delta and p38 MAP kinase. Cell Immunol 2008 May;253(1-2):45-53.
  136. 136. Mischiati C, Pironi F, Milani D, Giacca M, Mirandola P, Capitani S, et al. Extracellular HIV-1 Tat protein differentially activates the JNK and ERK/MAPK pathways in CD4 T cells. AIDS 1999 Sep 10;13(13):1637-45.
  137. 137. Mishra S, Mishra JP, Kumar A. Activation of JNK-dependent pathway is required for HIV viral protein R-induced apoptosis in human monocytic cells: involvement of antiapoptotic BCL2 and c-IAP1 genes. J Biol Chem 2007 Feb 16;282(7):4288-300.
  138. 138. Muthumani K, Choo AY, Hwang DS, Premkumar A, Dayes NS, Harris C, et al. HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Blood 2005 Sep 15;106(6):2059-68.
  139. 139. Renga B, Francisci D, D'Amore C, Schiaroli E, Mencarelli A, Cipriani S, et al. The HIV matrix protein p17 subverts nuclear receptors expression and induces a STAT1-dependent proinflammatory phenotype in monocytes. PLoS One 2012;7(4):e35924.
  140. 140. Yang X, Gabuzda D. Regulation of human immunodeficiency virus type 1 infectivity by the ERK mitogen-activated protein kinase signaling pathway. J Virol 1999 Apr;73(4):3460-6.
  141. 141. Federico M, Percario Z, Olivetta E, Fiorucci G, Muratori C, Micheli A, et al. HIV-1 Nef activates STAT1 in human monocytes/macrophages through the release of soluble factors. Blood 2001 Nov 1;98(9):2752-61.
  142. 142. Kohler JJ, Tuttle DL, Coberley CR, Sleasman JW, Goodenow MM. Human immunodeficiency virus type 1 (HIV-1) induces activation of multiple STATs in CD4+ cells of lymphocyte or monocyte/macrophage lineages. J Leukoc Biol 2003 Mar;73(3):407-16.
  143. 143. Percario Z, Olivetta E, Fiorucci G, Mangino G, Peretti S, Romeo G, et al. Human immunodeficiency virus type 1 (HIV-1) Nef activates STAT3 in primary human monocyte/macrophages through the release of soluble factors: involvement of Nef domains interacting with the cell endocytotic machinery. J Leukoc Biol 2003 Nov;74(5):821-32.
  144. 144. Selliah N, Finkel TH. HIV-1 NL4-3, but not IIIB, inhibits JAK3/STAT5 activation in CD4(+) T cells. Virology 2001 Aug 1;286(2):412-21.
  145. 145. Vyakarnam A, Matear P, Meager A, Kelly G, Stanley B, Weller I, et al. Altered production of tumour necrosis factors alpha and beta and interferon gamma by HIV-infected individuals. Clin Exp Immunol 1991 Apr;84(1):109-15.
  146. 146. Herbein G, Gras G, Khan KA, Abbas W. Macrophage signaling in HIV-1 infection. Retrovirology 2010;7:34.
  147. 147. Bromberg J, Darnell JE, Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 2000 May 15;19(21):2468-73.
  148. 148. Calo V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol 2003 Nov;197(2):157-68.
  149. 149. Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulation by cytokines. Drug News Perspect 2005 May;18(4):243-9.
  150. 150. Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 1997;15:563-91.
  151. 151. Darnell JE, Jr. STATs and gene regulation. Science 1997 Sep 12;277(5332):1630-5.
  152. 152. Lehtonen A, Matikainen S, Julkunen I. Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages. J Immunol 1997 Jul 15;159(2):794-803.
  153. 153. Lehtonen A, Matikainen S, Miettinen M, Julkunen I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol 2002 Mar;71(3):511-9.
  154. 154. Kohlhuber F, Rogers NC, Watling D, Feng J, Guschin D, Briscoe J, et al. A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses. Mol Cell Biol 1997 Feb;17(2):695-706.
  155. 155. Bovolenta C, Lorini AL, Mantelli B, Camorali L, Novelli F, Biswas P, et al. A selective defect of IFN-gamma- but not of IFN-alpha-induced JAK/STAT pathway in a subset of U937 clones prevents the antiretroviral effect of IFN-gamma against HIV-1. J Immunol 1999 Jan 1;162(1):323-30.
  156. 156. Warby TJ, Crowe SM, Jaworowski A. Human immunodeficiency virus type 1 infection inhibits granulocyte-macrophage colony-stimulating factor-induced activation of STAT5A in human monocyte-derived macrophages. J Virol 2003 Dec;77(23):12630-8.
  157. 157. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998;67:481-507.
  158. 158. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994 Aug 18;370(6490):527-32.
  159. 159. Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1998 Dec 8;1436(1-2):127-50.
  160. 160. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615-75.
  161. 161. Koyasu S. The role of PI3K in immune cells. Nat Immunol 2003 Apr;4(4):313-9.
  162. 162. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 2001;70:535-602.
  163. 163. Deane JA, Fruman DA. Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu Rev Immunol 2004;22:563-98.
  164. 164. Sasaki T, Suzuki A, Sasaki J, Penninger JM. Phosphoinositide 3-kinases in immunity: lessons from knockout mice. J Biochem 2002 Apr;131(4):495-501.
  165. 165. Liu H, Perlman H, Pagliari LJ, Pope RM. Constitutively activated Akt-1 is vital for the survival of human monocyte-differentiated macrophages. Role of Mcl-1, independent of nuclear factor (NF)-kappaB, Bad, or caspase activation. J Exp Med 2001 Jul 16;194(2):113-26.
  166. 166. Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, Planelles V, Maggirwar SB, Dewhurst S, et al. Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology 2008;5:11.
  167. 167. Huang Y, Erdmann N, Peng H, Herek S, Davis JS, Luo X, et al. TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation. J Immunol 2006 Aug 15;177(4):2304-13.
  168. 168. Cowan KJ, Storey KB. Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol 2003 Apr;206(Pt 7):1107-15.
  169. 169. Zhang YL, Dong C. MAP kinases in immune responses. Cell Mol Immunol 2005 Feb;2(1):20-7.
  170. 170. Dong C, Davis RJ, Flavell RA. Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase. J Clin Immunol 2001 Jul;21(4):253-7.
  171. 171. Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol 2002;20:55-72.
  172. 172. Nishimoto S, Nishida E. MAPK signalling: ERK5 versus ERK1/2. EMBO Rep 2006 Aug;7(8):782-6.
  173. 173. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 1997 Aug;9(5):337-51.
  174. 174. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, et al. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 1996 Jun 3;15(11):2760-70.
  175. 175. Hale KK, Trollinger D, Rihanek M, Manthey CL. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol 1999 Apr 1;162(7):4246-52.
  176. 176. Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal 2000 Jan;12(1):1-13.
  177. 177. Ashwell JD. The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 2006 Jul;6(7):532-40.
  178. 178. Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 1994 May 12;369(6476):156-60.
  179. 179. Rouse J, Cohen P, Trigon S, Morange M, onso-Llamazares A, Zamanillo D, et al. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 1994 Sep 23;78(6):1027-37.
  180. 180. Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 1997 Nov;17(11):6508-16.
  181. 181. Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 1993 Nov;7(11):2135-48.
  182. 182. Zhang S, Liu H, Liu J, Tse CA, Dragunow M, Cooper GJ. Activation of activating transcription factor 2 by p38 MAP kinase during apoptosis induced by human amylin in cultured pancreatic beta-cells. FEBS J 2006 Aug;273(16):3779-91.
  183. 183. Evans P, Sacan A, Ungar L, Tozeren A. Sequence alignment reveals possible MAPK docking motifs on HIV proteins. PLoS One 2010;5(1):e8942.
  184. 184. Gee K, Angel JB, Mishra S, Blahoianu MA, Kumar A. IL-10 regulation by HIV-Tat in primary human monocytic cells: involvement of calmodulin/calmodulin-dependent protein kinase-activated p38 MAPK and Sp-1 and CREB-1 transcription factors. J Immunol 2007 Jan 15;178(2):798-807.
  185. 185. Saxena M, Busca A, Pandey S, Kryworuchko M, Kumar A. CpG protects human monocytic cells against HIV-Vpr-induced apoptosis by cellular inhibitor of apoptosis-2 through the calcium-activated JNK pathway in a TLR9-independent manner. J Immunol 2011 Dec 1;187(11):5865-78.
  186. 186. Muthumani K, Choo AY, Shedlock DJ, Laddy DJ, Sundaram SG, Hirao L, et al. Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J Virol 2008 Dec;82(23):11536-44.
  187. 187. Alhetheel A. HIV-induced dysregulation of IFN-gamma signaling and programmed cell death in human primary monocytes. Ph D Thesis, 2010.

Written By

Abdulkarim Alhetheel, Mahmoud Aly and Marko Kryworuchko

Submitted: 07 May 2012 Published: 10 April 2013