Herpes Simplex Virus: The Interplay Between HSV,Host,and HIV-1

Abstract

Herpes simplex virus proteins interact with host (human) proteins and create an environment conducive for its replication. Genital ulceration due to herpes simplex virus type 2 (HSV-2) infections is an important clinical manifestation reported to increase the risk of human immunodeficiency virus type 1 (HIV-1) acquisition and replication in HIV-1/HSV-2 coinfection. Dampening the innate and adaptive immune responses of the skin-resident dendritic cells, HSV-2 not only helps itself, but creates a “yellow brick road” for one of the most dreaded viruses HIV, which is transmitted mainly through the sexual route. Although, data from clinical trials show that HSV-2 suppression reduces HIV-1 viral load, there are hardly any reports presenting conclusive evidence on the impact of HSV-2 coinfection on HIV-1 disease progression. Be that as it may, understanding the interplay between these three characters (HSV, host, and HIV-1) is imperative. This review endeavors to collate studies on the influence of HSV-derived proteins on the host response and HIV-1 replication. Studying such complex interactions may help in designing and developing common strategies for the two viruses to keep these “partners in crime” at bay.

Introduction

Human immunodeficiency virus type 1 (HIV-1), belonging to the genus Lentivirus under the family Retroviridae, causes deterioration of the immune system leading to acquired immune deficiency syndrome (AIDS), characterized by opportunistic infections that are generally seen in immunocompromised individuals. Presence of other sexually transmitted infections increase the risk of acquiring HIV-1, mainly due to the clinical and immunological manifestations. Many studies have been carried out to reveal the association and patterns of sexually transmitted infections in people living with HIV/AIDS. Epidemiological data prove that sexually transmitted infections causing genital ulcerations (herpes and syphilis) are associated with HIV/AIDS (45). Many clinical trials have also evaluated the effect of HSV-2 suppressive therapy and HIV-1 viral load. These studies have shown that acyclovir/valacyclovir used to treat Herpes reduced HIV-1 seminal and plasma viral load. These studies have been carefully evaluated and presented in many reviews (7,104) and are therefore beyond the scope of this review. This review focuses on two aspects: influence of HSV infection on host signaling pathways and the effects of such perturbations that may be responsible for HIV-1 replication and persistence within the human host, and interaction between HSV and host proteins resulting in inflammation and recruitment of HIV-1 target cells that increase HIV-1 acquisition. Although such interactions are easier to study in circumstances of monoinfection, it is rather difficult to discern the role of signaling pathways in case of dual infections. This is mainly because the two viruses may not infect the same cell type. In the case of HSV and HIV-1 coinfection, immune cells such as dendritic cells (DCs) (17,18,67) and macrophages (66) are most extensively studied, as they can be coinfected with both viruses, while their interactions in T cells (50) are less explored. In vitro studies have also focused on DC T cell co-culture experiments to study the interaction between HSV-infected DCs on HIV-1-infected T cells (67). A clear understanding of such complex multicellular networks and the way viral proteins interact with these pathways is essential and is the principal aim of this review.

HSV Biology and Sexual Transmission

HSV-1 and HSV-2 belong to the genus Simplex virus within the subfamily Alphaherpesvirinae under the family Herpesviridae (20). They are transmitted mainly through the orofacial and sexual route, respectively, leading to the formation of ulcerative lesions. The infective lesions heal, and the symptoms subside. The virus then migrates within the nearest ganglia (lumbosacral dorsal root or trigeminal ganglia) and establishes latency (20,52). However, during immune suppression, the virus reactivates and migrates to the site of entry. Sometimes, the lytic cycle triggered in the brain can cause serious complications such as encephalitis, which is mainly reported in children (9,15). Although the majority of sexual transmission of herpes is caused by HSV-2, genital ulcerations due to HSV-1 have also been reported. Studies indicate a paradigm shift from HSV-2 to HSV-1 as a cause of genital ulcers in the United States (85,112), Australia (38), and the Netherlands (99). Therefore, this review collectively refers to both viruses as HSV. However, where the two viruses show a different mechanism of action, the precise phenomenon with respect to each virus is described.

HSV and Host Protein Interaction: Entry and Replication

Interaction of HSV with the host begins at the cell surface where the glycoprotein studded envelope interacts with the host receptors. HSV harbors around eight different glycoproteins of which glycoprotein B (gB), gD, and hetero oligomers gH-gL are important in virus entry. Of others, the gC glycoprotein is involved in preventing the virolysis mediated by the host complement system (49). HSV uses many receptors—herpes virus entry mediators (HVEM) belonging to the tumor necrosis factor (TNF) super family, and nectin-1 and nectin-2 belonging to the immunoglobulin (Ig) super family receptors and the 3-O-sulfated heparin sulfate (46,59,106). Although the interaction of the host receptors with the virus is known, their precise role in facilitating viral entry are yet to be fully elucidated. Cheshenko et al. showed that glycoprotein gB and Akt (protein kinase B) physically interact, resulting in calcium release near the plasma membrane, and may facilitate the viral entry (14).

Post entry into the cells, the DNA infiltrates within the nucleus and replicates in discrete loci (26). The promyelocytic leukemia nuclear bodies (PML-NBs) or nuclear domains (ND-10) implicated in many host cellular functions (37,57,63,93) are recruited to these sites in order to repress viral replication. This section specifically emphasizes on the function of the HSV-infected cell proteins (ICP0 and ICP27), related to their importance in HSV replication by disturbing the normal cellular functions.

The first protein of the series, ICP0, is an immediate early protein of HSV and is responsible for transactivation of viral gene expression during lytic replication (26). Studies have shown that quiescent HSV genomes reside within ND-10, creating difficulties for ICP0 to access viral genomes and activate transcription (26). With a ubiquitin ligase activity, ICP0 has been shown to be involved in small ubiquitin-like modifier (SUMO) targeted protein destruction of the cellular proteins that are involved in cellular transcription, survival, and apoptosis (26). Thus, by localizing within the ND-10, ICP0 mediates ND-10 destruction by SUMO modification of Sp100 by the proteasomal pathway and activates HSV replication (25 –27). It has been reported that HSV ICP0 mutants attenuated for SUMO interaction repress HSV infection and mediate resistance to intrinsic antiviral mechanisms against HSV (56). The activity of ICP0 protein is mainly governed by the phosphorylation and has three phosphorylation sites: 224–232, 365–371, and 508–518 (16,73). A study carried out by Jung et al. showed that besides ICP0, Us3 kinase is also responsible for disruption of PML-NBs in a kinase and proteasomal-dependent manner. This in turn affects the intrinsic antiviral defense and makes the histone deacetylases (HDAC-1 and HDAC-2) available for phosphorylation, so as to avoid transcriptional silencing of the viral genome (43), an activity reported to exist in many distantly related alphaherpesviruses (93).

ICP0 also has a potent transactivating potential. Studies have shown that transcription of HIV-1 provirus can be stimulated by HSV infection (1). The stimulation primarily occurs at the level of transcriptional activation of the HIV-1 long terminal repeat (LTR) and is mediated by both cellular and HSV encoded transactivators (1,96). HSV ICP0 cooperates effectively with the HIV-1 transactivator, Tat, in the stimulation of HIV-1 LTR-directed transcription. The cooperation between ICP0 and Tat is specific for the HIV-1 LTR and has not been observed with other promoters (96). Further analyses of HIV-1 LTR deletion mutants showed that ICP0 not only transactivates HIV-1 LTR mutant that is unresponsive to NF-kB and Tat-mediated transactivation, but also restores responsiveness to Tat (96). Earlier studies carried out by Popik and Pitha showed that NF-κB and Tat were important for HSV-induced activation of HIV (88).

The second HSV protein, ICP27, is an immediate early regulatory phosphoprotein, homologous to gene products identified in all classes of herpes viruses so far (100). ICP27 is a multifunctional protein involved in transcription, mRNA export (100), regulation of other HSV proteins (105), and more recently in virus release (82). ICP27 has been implicated in altering the splicing of selective cellular pre-mRNAs and diverting the cellular transcription machinery toward the synthesis of early and late viral proteins (77). ICP27 also promotes shuttling of viral mRNA by utilizing the cellular export machinery. This function is triggered by binding of ICP27 to proteins of the transcription-export (TREX) complex, in particular to REF/Aly, which directs viral mRNA to the TAP/NFX1 pathway (39,107). A recent comparative study between HSV-1 and HSV-2 ICP27 homolog has highlighted the role of HSV ICP27 protein in virus release, which was mapped to the amino terminal region of the protein (82).

Although ICP27 majorly functions using the TAP/NFX-1 pathway, other pathways utilizing the chromosome region maintenance (CRM1) protein is also involved in transporting cellular and viral transcripts. First identified in HIV-1 Rev, a leucine rich nuclear export signal (NES) with the ability to interact with the CRM-1 protein is required for nuclear transport (3). Subsequently, many HSV proteins have also been shown to contain leucine-rich NES that can interact with CRM-1 (32). Whether CRM-1 plays any role in HSV infection is, however, unclear. A study by Park et al. showed that ICP27 from HSV-1 is sensitive to leptomycin B (LMB), a specific inhibitor of the CRM-1 protein. However, ICP27 from HSV-2 is naturally resistant to this inhibitor (83). LMB treatment blocks the production of late viral proteins and prevents virion release, although the exact mechanism is still unclear. A previous study by the same group showed that LMB treatment of HSV-1 blocks nuclear translocation of proteins ICP0 and ICP4, suggesting that LMB sensitivity or resistance by HSV is probably a multifactorial trait (54). Although it has been shown that NES present on ICP27 is specific for the NFX1 interaction (13), there is no clear evidence showing physical interaction between ICP27 and CRM-1 aiding Rev independent export and thus increasing HIV-1 transcription. This would be an interesting aspect to explore, as it may have implications in HIV-1/HSV-2 coinfections.

HSV and Cell Cycle: Cutting Corners for Survival

Controlled by a diverse signal transduction networks, the glycolysis and oxidative phosphorylation pathways help immune cells to proliferate in a relatively hypoxic environment of the inflamed or lymphoid tissues (1–5% oxygen tension) (30). This cascade of events, thus controlling the metabolic activity, is under the control of phospho-inositide dependent kinase (PDK1), protein kinase B (AKT), and the mammalian target of rapamycin complex (mTORC). The AKT pathway and its downstream effectors control numerous processes, which include cellular metabolism, apoptosis, and immune response (30). Apoptosis, autophagy, and necrotic pathway are important cellular processes that are interconnected to limit intracellular pathogens by killing the infected cells. Interaction of viral proteins with these molecules to inhibiting downstream signaling ensures effective virus replication and spread.

In the context of HSV, Dufour et al. showed that the ribonucleotide reductase R1 subunit of HSV has ability to protect cells from TNF-α and Fas ligand induced apoptosis by blocking the Caspase 8 activity (23). Further, this group also showed that this HSV protein can block poly I:C-induced apoptosis in HeLa cells by interfering with Toll–IL-1 receptor domain interaction (22). Apart from this protein, the HSV Us3 (serine threonine) kinase is also a key player in regulating cell death subsequent to HSV infection. Besides aiding the viral spread by cell-to-cell transmission via the formation of filamentous processes from infected cells (31), it is known to protect cells from apoptosis, DNA fragmentation, and condensation of the nuclei (8,32). It has been shown that Us3 protein prevents the phoshorylation of Bad, a mediator of apoptosis, thereby inactivating Bad (70). However, there are subtle variations in activities shown by the Us3 kinase in HSV-1 and HSV-2. It has been seen that abolishing Us3 activity in HSV-1 leads to virus accumulation in the perinuclear space while such changes were not noticed in HSV-2 (71).

Besides apoptosis, a self-degradation process called autophagy uses cues such as nutrient stress to manage energy resources of cells during the development process, as well as aids clearing of misfolded proteins, damaged organelles, and intracellular pathogens (36). MTOR and PKR-eLF2α are important pathways downstream of AKT that control autophagy (36). Double-stranded RNA (dsRNA) dependent protein kinase (PKR) located upstream of Beclin-1 is interferon induced and plays an important role in antiviral defense (64). The HSV proteins Us11 and ICP34.5 have been shown to play an important role is controlling autophagy. Us11, a dsRNA binding protein associated with ribosome, directly interacts with PKR (64). ICP34.5 on the other hand contains two domains the C terminal GADD34 domain and N-terminal domain that are involved interaction with PKR and Beclin-1, respectively (80). The former (GADD34 domain) recruits protein phosphates 1 (PP-1) to inhibit PKR-mediated eLF2α phosphorylation (55), while the latter interacts directly with Beclin-1 to block autophagy (80). Taken together, this shows that the host has multiple pathways to induce apoptosis and autophagy in infected cells and that HSV strategically uses its arsenal of proteins that target various steps in these pathways to ensure viral replication and spread.

AKT can be activated by phosphorylation by modulators other that than PI3-K. The Src family kinase (SFK) has been shown to activate AKT (84). The HSV tegument protein VP11/12, modulate this host cell signaling pathways by binding to the Src family kinase (SFK) Lck and thus activate the AKT during HSV-1 infection (110). This activation was specifically observed in the T lymphocytes but not in epithelial cells or fibroblasts (110). Further, the study defined role of VP11/12 SFK-binding motifs in the recruitment and activation of SFKs, which directly or indirectly lead to phosphorylation of the additional motifs involved in recruiting p85, Grb2, and Shc (102) known to activate AKT. Considering the fact that this VP11/12 mediated activation of AKT was only seen in T lymphocytes, its implications on HIV-1 replication need to be investigated.

Other proteins involved in cell growth, proliferation, and DNA repair have also been implicated to influence viral kinetics. Protein p53 and its downstream molecule p21, which are known DNA repair markers, have been shown to aid HSV replication. Studies conducted by Zhou et al. reported high HSV-2viral titer in p53 (+/+) mice but not in p53 (–/–) strains. This is one of the proposed mechanisms by which HSV-2 arrests cells in the G0/G1 phase during initial infection (86). Thus, by interacting with various proteins downstream of AKT that are involved in cell cycle, apoptosis, and autophagy, HSV effectively uses its proteins to sabotage the host signal transduction pathways for its benefits.

HSV and Immune Signaling

The innate immune signaling is the first line of defense against the incoming virus and limits virus multiplication before the adaptive immune responses take over. This is a complex mechanism involving macrophage, DCs, and NK cells. Many infections alter the NK cell phenotype during the early phase of infection resulting in defective viral clearance. Based on the evidence of NK cell characterization in HSV infection, the NK cell repertoire remains unaltered (10). However, in order to evade immune surveillance by the skin resident DCs, HSV-2 decreases HLA-C expression in infected cells and makes it susceptible to NK cell–mediated destruction (24). In addition to NK cells, mast cells also respond to incoming foreign antigen by secretion of histamines via degranulation. Aoki et al. showed that mice deficient in mast cells have increased HSV-2 viral titer, disease severity, and mortality. However, when such mice were inoculated with bone marrow–derived mast cells, this triggered a release of TNF-α and IL-6 and protected mice from HSV-2-induced mortality without triggering degranulation (2).

Innate immune signaling functions by recognition of pathogen associated molecular patterns (PAMPs) in order to stimulate the secretion of interferon (IFN) alpha, beta, or gamma along with other cytokines (103). The INF secretion is mainly stimulated by interaction of PAMPs via Toll-like receptors (TLRs), which recognize different ligands (103). During HSV infection, TLRs— TLR2, TLR3, and TLR9—are partially responsible for activating and inducing cytokine production (72). Interaction of HSV particles with TLR2 activates NF-κB, while interaction of unmethylated CpG motifs from HSV DNA with TLR9 uses the MyD88 pathway for induction of IFN-α/β, TNF-α, and RANTES (65). Malmgaard et al. showed that various mechanisms of pathogen recognition during HSV infection may or may not be dependent on TLR signaling and are influenced by steps such as virus entry and replication. The induction of immune modulators TNF-α and RANTES is dependent on MyD88 expression, while IFN is independent of expression of MyD88 (65). Mounting evidence suggests that the virus encoded virion host shut-off (Vhs) protein might be responsible for counteracting the effect (74). This protein is present as a part of the tegument within the virus and enters the cytoplasm upon viral entry. Using murine model, Murphy et al. showed that Vhs-deficient HSV show a 1,000-fold reduction in the number of viral particles than in wild type mice. However, the Vhs mutant HSV replicated relatively well in IFNα/β/R^–/– mice compared with its wild type counterpart. The data suggest that Vhs counteracts only with the innate defenses, not with the adaptive immune signaling (74). Yao and Rosenthal have shown that Vhs protein suppresses IFN response by selectively downregulating TLR-2, TLR-3, RIG1, and Mda-5, involved in sensing dsRNA (113). Many studies have also highlighted the fact that Vhs protein derived from HSV-2 is more potent than HSV-1, which makes HSV-2 more resistant to IFN-α/β (29,48,75). TLR-3 recognizes dsRNA is more important for protection against herpes simplex encephalitis (HSE) in children (35). Experiments conducted in mice (90) suggested that astrocytes require an intact TLR3 to mediate resistance to HSV infection. However, studies carried out in human-induced pluripotent stem cells (53) showed that TLR-3 deficiency and UNC-93-B^–/– deficient neurons and oligodendrocytes were more susceptible to HSV-1 infection than control cells. Such changes in susceptibility to HSV infection were not noted in astrocytes (53). This is indicative of the fact that although TLR-3 may be important to protect neuronal cells from HSV infection, TLR-3-independent antiviral defenses may also play a role in resistance to HSV infection in astrocytes.

TLR-independent mechanisms, involving DNA sensing by stimulator of interferon genes (STING) or NOD like Pathway (NLR) are also present for stimulation of IFN production in response to infection by intracellular pathogens (6). HSV infection studies carried out by Ishikawa et al. in STING^−/− and wild type mice highlight the importance of STING in protection against lethal HSV infection (42). This study along with others shows that STING, which is expressed in many cell types of mouse (28) and human lineage (51), is important for the control of HSV infection. A study published by Kalamvoki et al. goes a step further to show that ICP0 is required for stabilization of STING. Using wild type and ΔICP0 HSV cultures produced in Hep2 cells, they showed that unlike ΔICP0 cultures, STING is transferred from Hep2 cells infected with wild type HSV to Vero cells via exosomes along with viral particles, viral mRNAs, and miRNAs (44). The authors identified a novel strategy used by HSV to control replication in neighboring cells within the mucosa and the central nervous system, in order to increase transmission (30).

Interferon regulatory factors (IRF)—mainly IRF-3 and IRF-7—and important for stimulation of interferon α/β and other interferon stimulated genes (ISGs) (6). DNA-dependent activator of interferon regulatory factor (DAI), also known as DLM-1 or ZBP-1, is a DNA sensor that that stimulates IFN responses by triggering NF-κB and IRF-3 (6). This activity is, however, cell-type dependent in both mice (34) and humans (87) due to redundancy in DNA sensing systems. Using confocal microscopy and Co-IP experiments, Pham et al. showed that DAI directly interacts with ICP0. This interaction decreased ICP0 promoter expression, consequently reducing the E3 ligase activity of ICP0 on PML, crucial for efficient HSV replication (87). However, the study also highlighted that DAI was not actually required for production of IFN responses in HepG2 cells (58) and that the activity of DAI is cell-type dependent. This is also supported by a study showing that the RING finger domain of ICP0 blocks the localization of the key IRF-3 and −7 into the nucleus, thereby preventing expression of ISGs in HEK cells (43). This action is suggested to be mediated by the E3-ubiquitin activity of the protein (58,81,93). On the other hand, the ICP34.5 protein of HSV-1 contains a TANK binding kinase −1 (TBK-1) domain that overlaps with the Beclin-1 binding domain (55) disrupts TBK-1/IRF-3 interaction to inhibit interferon production (109).

The literature reviewed thus substantiates that HSV has evolved several mechanisms that help it to disturb normal cellular functioning and innate immune signaling, which is the first line of defense against intracellular pathogens, summarized in Figure 1.

FIG. 1.

The effects of herpes simplex virus (HSV) proteins on host cellular functioning and antiviral defense. HSV enters cells by interacting with the cell surface receptors. Post entry, the tegument protein such as Vhs is released in the cytoplasm and interferes with the DNA and dsRNA sensing pathways in the host. The HSV DNA replicates in specialized sites within the nucleus, and the promyelocytic leukemia nuclear bodies (PML-NBs; ND-10) are recruited to repress replication. HSV proteins (ICP0 and Us3) help the destruction of ND-10 and aid viral replication. ICP0, a potent transactivator of HSV gene expression, also interferes with interferon (IFN) signaling and blocks innate defenses against the incoming virus. Immediate early protein, ICP27, interferes with the spliceosome assembly and inhibits host mRNA splicing and helps shuttling HSV mRNAs. HSV US3 kinase and the ribonucleotide subunit (R1) block apoptosis and INF induction by inhibiting the functions of Bad (apoptotic protein) and IRF-3/IRF7, respectively.

Cell-mediated immunity, an arm to adaptive immune response, is an important mechanism elicited by effective presentation of antigens to CD8+ T cells. Antigen presentation through MHC-I molecules of the surface of virally infected cells to CD8+ T cells helps eradicate infected cell population to limit viral spread. In order to evade host immunity, viruses have evolved mechanisms to counteract antigen presentation. Røder et al. has summarized mechanisms developed by herpesviruses to inhibit effective antigen presentation in their review (92). The HSV proteins ICP47 and Us3 influences MHC-I presentation either directly or indirectly, thereby evading HSV-specific CD8+ T cell mediated lysis (41,92). While influencing HSV-specific CD8 T cell responses, it is not known whether such interactions can also stimulate bystander CD8 T cells and weaken T cell function. This would be of interest in HIV-1/HSV2 coinfected individuals, as a study carried out by Sheth et al. in HIV-1 and HSV-2 coinfected MSM cohort, in Canada, showed impaired HIV-1-specific CD8 T cell function in coinfected individuals. The weakened cell function observed in the study was associated with CD38 expression (98), but the possible mechanisms underlying such changes have been largely unexplored. In vitro studies focusing on the effects of altered expression and activation of T cells due to HSV/HIV-1 coinfection in a single or a dual cell culture system (DC T cells and cervical explants) and there clinical significance will help to address this question.

HSV Infection of Genital Mucosa: Recruitment of HIV-1 Target Cells

It is known that HSV-2 increases the risk of acquiring and transmitting HIV-1 (91). Studies have shown that HSV infection increases HIV-1 viral load (21,91,95). Many groups have therefore focused on this aspect and have tried hypothesizing the mechanisms by which HSV-2 might accomplish this increase. HSV-2 entry receptors are constitutively expressed on the immune cells, thereby allowing the uptake of HSV-2 (46). Using real-time polymerase chain reaction, Sartori et al. reported that HSV-2 upregulated expression of CCR5, a coreceptor essential for HIV entry in macrophages (94). As most of the primary HIV infections have been attributed to CCR5 tropic viruses (66), this study provided one of the possible mechanisms by which HSV-2 increases the chances of acquiring HIV (66). Langerhan cells (LCs) prevent HIV-1 transmission via the C-type lectin, langerin, which targets the virus for degradation (19), thereby reducing HIV-1 transmission to T cells. De Jong et al. showed that HSV-2 increases susceptibility of LCs to HIV-1 by downregulating langerin expression. Also, the HSV released by infected LCs compete with HIV-1 for langerin binding. This allows HIV-1 to infect LCs efficiently and transmit infection to T cells (18). A study carried out by Ogawa et al. showed that relatively few LCs exist that are coinfected by both viruses. They also showed that HSV-2-infected keratinocytes secrete human β defensins and LL-37 protein. This is in turn responsible for increasing the expression of HIV-1 receptors on LCs (79). Taken together, the above findings suggest that HSV-2 not only inhibits langerin function but also increases the susceptibility of LCs to HIV-1 infection. T cells, which are an essential target for HIV-1 infection, migrate to the genital and mucosal tissue under the influence of the chemokine CXCL-9 (111). Huang et al. showed that HSV-2 seropositivity was associated with higher levels of CXCL-9 in cervical mucus samples. This was also evidenced by in vitro HSV-2 infection experiments in vaginal epithelial cells using transwell co-culture models (40).

One of the studies focuses on the DCs that form a link between the innate and adaptive immune responses. DCs at the site of entry of HSV-2 and HIV-1 contribute to viral spread in the mucosa. The DC-specific C-type lectin DC-SIGN are the receptors through which DCs become infected with HSV and transmit infection to permissive cell targets (17). Upon infection, HSV exhibits immune modulatory effect dampening the DC maturation and reducing the expression of costimulatory signals (86,101). Martinelli et al. provided in vivo data showing an increased percentage of α4β7^high CD4+ T cells in rectal mucosa, iliac lymph nodes, and blood of macaques exposed to HSV-2 at the rectal mucosa. The group subsequently proved that HSV-2-infected immature monocyte-derived DCs (moDCs) induced expression of aldehyde dehydrogenase ALDH1A1, an enzyme essential for retinoic acid (RA) production (97) in a dose-dependent manner. Moreover, HSV-2-infected moDCs significantly increased α4β7 expression when co-cultured with CD4+ T lymphocytes, thereby increasing the HIV-1 infection in a RA-dependent manner (67,76).

Thus, the above literature substantiates the viral synergy between HSV-2 and HIV-1 sexual transmission, providing evidence of how HSV-2 infection accelerates HIV-1 acquisition mainly through recruitment of CD4 T cells and increasing the expression of receptors essential for HIV-1 infection on cells localizing at the site of entry. These changes in cellular events unfolding within the genital mucosa due to HSV-2 infection are described in Figure 2. Such events inadvertently create a microenvironment able to assist efficient HIV-1 infection.

FIG. 2.

HSV-2 infection creates a microenvironment in the genital mucosa favorable for human immunodeficiency virus type 1 (HIV-1) infection. (A) Infection of the skin-resident macrophage increases the expression of the CCR5 receptors, which aids the early transmitted R5 tropic HIV-1. (B) Upregulation of CD4 and CCR5 receptors due to LL-37 secretion from epithelial cells and downregulation of langerin due to HSV-2 infection helps HIV-1 to establish infection in Langerhan cells (skin-resident dendritic cells). (C) The HSV-2-infected dendritic cells migrating to the proximal lymph nodes secrete retinoic acid, imparting the gut phenotype (α4β7^high, CCR9) on naïve T cells, enabling them to infiltrate the genital mucosa. This causes a high number of CD4 T cell infiltrations in the mucosal tissue. T cell migration is further potentiated due to the secretion of CXCl-9 chemokine from the infected epithelial cells. The direct influence of HSV-2 on expression of genes essential for HIV-1 to replicate in T cells has not yet been investigated.

Discussion

HSV is an important pathogen in the context of HIV-1 infection. Clinical trials for assessing the efficacy of HSV drug therapies in HSV-2 and HIV-1 coinfected individuals have been carried out. Some of the trials have shown that effective suppression of HSV-2 may help in decreasing the HIV-1 plasma viral load (5,12,60,89)and slow down disease progression (60,89), but some could not reach a conclusion (75). In vitro studies have shown that acyclovir can act as a potent HIV-1 reverse transcriptase (RT) inhibitor and inhibit many lab-adapted, primary, and drug-resistant HIV-1 isolates (62,68,69). This effect has been shown to be potentiated with the use of ribavirin, an antiviral used to treat hepatitis (108). As with any antiretroviral drug, there is always a chance of selecting drug-resistant mutants due to the continuous evolution to HIV-1. However, studies carried out by Baeten et al. show that HSV-2 suppressive therapy using acyclovir or valacyclovir does not select for HIV-1 drug-resistant mutants (4), but an in-vitro study has shown that a HIV mutant harboring the V75I mutation was inhibited by substantially higher amounts of acyclovir (69). Looking at this scenario, studies on understanding the interaction between the two viruses within the host are essential.

This review has thus focused on the interactions between HSV and important host proteins, and their effect in altering both innate and adaptive host responses, which allow the virus to establish a lifelong infection within the human host. The ability of HSV-2 to prevent an effective immune response at the site of entry renders the host susceptible to other viral and bacterial infections. The most important aspect in coinfections is that these perturbations allow HIV to spread easily and effectively within the host. Studies have shown the importance of innate signaling in the effective control of HIV-1 during the early phase of infection. The resident immune cells effectively clear the virus in a well-coordinated manner. The IFNα/β response is very crucial for controlling viral infections, which is true of HIV-1 as well (28,89). However, the presence of HSV-2 malfunctions against the human host and allows easy access to HIV at the genital mucosa. HSV tegument proteins have the ability to phosphorylate AKT and influence viral entry as well as replication. Constitutive activation of AKT by HSV has negative implications on virally infected cells, which allow them to produce more viral progeny during the early infection stage (78). HIV-1 proteins such as gp120, Tat, and Nef have also been shown to affect the AKT pathways, resulting in inhibition of apoptosis and autophagy (33,61). Whether the presence of HSV-2 enhances this effect by acting in coordination with HIV-1 and blocking various steps in the initiation of apoptosis is yet to be understood. Studies have also shown that HSV-2 proteins can regulate the expression of many host genes either positively or negatively. Recent studies have identified that certain host genes are crucial for HIV-1 replication within its target CD4+ T cells (11,47,114). If HSV-2 has the ability to influence these genes, it may increase the replication kinetics of HIV-1. Although HSV is known to infect many cell types (46), reports indicating HSV-2 infection in primary CD4 T-cells (50) are rare. Whether HSV-2 directly influences T cells or exerts its effect through cytokine and chemokine signaling from the infected genital epithelial and immune cells or by defective cell signaling cascade is still unclear, and research in that direction may be help answer some of these questions.

Conclusion

A substantial amount of evidence is available on the interaction between HSV and HIV-1. Many epidemiological and molecular data sets have shown the association between these sexually transmitted pathogens. Basic science research in the field of HSV infection has increased the understanding of the HSV–host interactive biology. This information collated together with the knowledge of HIV pathogenesis will help a clear picture to be obtained of how the two viruses interact within the host and benefit each other. Many factors described in this review play an important role in HSV/HIV-1 viral synergy and thus increase the knowledge of important mechanisms that may help to achieve effective control of HIV-1 as well as HSV.

Footnotes

Acknowledgments

The authors would like to acknowledge the assistance of Director, NARI, for critical review of the manuscript. The authors also wish to thank the Indian Council of Medical Research for funding the intramural project entitled “HIV-1-HSV2 Coinfections.”

Author Disclosure Statement

No competing financial interests exist.

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