Transmission Of Simian Immunodeficiency Virus Research Articles

Vaccine plus microbicide effective in preventing vaginal SIV transmission in macaques

The human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV)mac251 acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIVmac251, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected. In an arm of 18 vaccinated-only animals without microbicide, 40% of macaques remained uninfected. The combined SAMT-247/vaccine regimen was significantly more effective than vaccination alone. By analysing immune correlates of protection, we show that, by increasing zinc availability, SAMT-247 increases natural killer cytotoxicity and monocyte efferocytosis, and decreases T-cell activation to augment vaccine-induced protection.

Walk on the wild side: SIV infection in African non-human primate hosts-from the field to the laboratory.

HIV emerged following cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect non-human primates (NHPs) from Africa. While HIV replication and CD4+ T-cell depletion lead to increased gut permeability, microbial translocation, chronic immune activation, and systemic inflammation, the natural hosts of SIVs generally avoid these deleterious consequences when infected with their species-specific SIVs and do not progress to AIDS despite persistent lifelong high viremia due to long-term coevolution with their SIV pathogens. The benign course of natural SIV infection in the natural hosts is in stark contrast to the experimental SIV infection of Asian macaques, which progresses to simian AIDS. The mechanisms of non-pathogenic SIV infections are studied mainly in African green monkeys, sooty mangabeys, and mandrills, while progressing SIV infection is experimentally modeled in macaques: rhesus macaques, pigtailed macaques, and cynomolgus macaques. Here, we focus on the distinctive features of SIV infection in natural hosts, particularly (1): the superior healing properties of the intestinal mucosa, which enable them to maintain the integrity of the gut barrier and prevent microbial translocation, thus avoiding excessive/pathologic immune activation and inflammation usually perpetrated by the leaking of the microbial products into the circulation; (2) the gut microbiome, the disruption of which is an important factor in some inflammatory diseases, yet not completely understood in the course of lentiviral infection; (3) cell population shifts resulting in target cell restriction (downregulation of CD4 or CCR5 surface molecules that bind to SIV), control of viral replication in the lymph nodes (expansion of natural killer cells), and anti-inflammatory effects in the gut (NKG2a/c+ CD8+ T cells); and (4) the genes and biological pathways that can shape genetic adaptations to viral pathogens and are associated with the non-pathogenic outcome of the natural SIV infection. Deciphering the protective mechanisms against SIV disease progression to immunodeficiency, which have been established through long-term coevolution between the natural hosts and their species-specific SIVs, may prompt the development of novel therapeutic interventions, such as drugs that can control gut inflammation, enhance gut healing capacities, or modulate the gut microbiome. These developments can go beyond HIV infection and open up large avenues for correcting gut damage, which is common in many diseases.

Genetic adaptations to SIV across chimpanzee populations.

Central and eastern chimpanzees are infected with Simian Immunodeficiency Virus (SIV) in the wild, typically without developing acute immunodeficiency. Yet the recent zoonotic transmission of chimpanzee SIV to humans, which were naïve to the virus, gave rise to the Human Immunodeficiency Virus (HIV), which causes AIDS and is responsible for one of the deadliest pandemics in human history. Chimpanzees have likely been infected with SIV for tens of thousands of years and have likely evolved to reduce its pathogenicity, becoming semi-natural hosts that largely tolerate the virus. In support of this view, central and eastern chimpanzees show evidence of positive selection in genes involved in SIV/HIV cell entry and immune response to SIV, respectively. We hypothesise that the population first infected by SIV would have experienced the strongest selective pressure to control the lethal potential of zoonotic SIV, and that population genetics will reveal those first critical adaptations. With that aim we used population genetics to investigate signatures of positive selection in the common ancestor of central-eastern chimpanzees. The genes with signatures of positive selection in the ancestral population are significantly enriched in SIV-related genes, especially those involved in the immune response to SIV and those encoding for host genes that physically interact with SIV/HIV (VIPs). This supports a scenario where SIV first infected the central-eastern ancestor and where this population was under strong pressure to adapt to zoonotic SIV. Interestingly, integrating these genes with candidates of positive selection in the two infected subspecies reveals novel patterns of adaptation to SIV. Specifically, we observe evidence of positive selection in numerous steps of the biological pathway responsible for T-helper cell differentiation, including CD4 and multiple genes that SIV/HIV use to infect and control host cells. This pathway is active only in CD4+ cells which SIV/HIV infects, and it plays a crucial role in shaping the immune response so it can efficiently control the virus. Our results confirm the importance of SIV as a selective factor, identify specific genetic changes that may have allowed our closest living relatives to reduce SIV’s pathogenicity, and demonstrate the potential of population genomics to reveal the evolutionary mechanisms used by naïve hosts to reduce the pathogenicity of zoonotic pathogens.

Role of Viral Protein U (Vpu) in HIV-1 Infection and Pathogenesis.

Human immunodeficiency virus (HIV)-1 and HIV-2 originated from cross-species transmission of simian immunodeficiency viruses (SIVs). Most of these transfers resulted in limited spread of these viruses to humans. However, one transmission event involving SIVcpz from chimpanzees gave rise to group M HIV-1, with M being the principal strain of HIV-1 responsible for the AIDS pandemic. Vpu is an HIV-1 accessory protein generated from Env/Vpu encoded bicistronic mRNA and localized in cytosolic and membrane regions of cells capable of being infected by HIV-1 and that regulate HIV-1 infection and transmission by downregulating BST-2, CD4 proteins levels, and immune evasion. This review will focus of critical aspects of Vpu including its zoonosis, the adaptive hurdles to cross-species transmission, and future perspectives and broad implications of Vpu in HIV-1 infection and dissemination.

A role for gorilla APOBEC3G in shaping lentivirus evolution including transmission to humans.

The APOBEC3 deaminases are potent inhibitors of virus replication and barriers to cross-species transmission. For simian immunodeficiency virus (SIV) to transmit to a new primate host, as happened multiple times to seed the ongoing HIV-1 epidemic, the viral infectivity factor (Vif) must be capable of neutralizing the APOBEC3 enzymes of the new host. Although much is known about current interactions of HIV-1 Vif and human APOBEC3s, the evolutionary changes in SIV Vif required for transmission from chimpanzees to gorillas and ultimately to humans are poorly understood. Here, we demonstrate that gorilla APOBEC3G is a factor with the potential to hamper SIV transmission from chimpanzees to gorillas. Gain-of-function experiments using SIVcpzPtt Vif revealed that this barrier could be overcome by a single Vif acidic amino acid substitution (M16E). Moreover, degradation of gorilla APOBEC3F is induced by Vif through a mechanism that is distinct from that of human APOBEC3F. Thus, our findings identify virus adaptations in gorillas that preceded and may have facilitated transmission to humans.

Marginal Effects of Systemic CCR5 Blockade with Maraviroc on Oral Simian Immunodeficiency Virus Transmission to Infant Macaques.

Current approaches do not eliminate all human immunodeficiency virus type 1 (HIV-1) maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV) mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures (P = 0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4+ T cells. Ramp-up viremia was significantly delayed (P = 0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had a marginal impact on acquisition and only a minimal impact on the postinfection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC.IMPORTANCE We have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof-of-concept study in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC-treated and naive infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment appears to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. New, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission.

SIVcpz closely related to the ancestral HIV-1 is less or non-pathogenic to humans in a hu-BLT mouse model

The HIV-1 pandemic is a consequence of the cross-species transmission of simian immunodeficiency virus in wild chimpanzees (SIVcpz) to humans. Our previous study demonstrated SIVcpz strains that are closely related to the ancestral viruses of HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) and two SIVcpz lineages that are not associated with any known HIV-1 infections in humans (SIVcpzMT145 and SIVcpzBF1167), all can readily infect and robustly replicate in the humanized-BLT mouse model of humans. However, the comparative pathogenicity of different SIVcpz strains remains unknown. Herein, we compared the pathogenicity of the above four SIVcpz strains with HIV-1 using humanized-BLT mice. Unexpectedly, we found that all four SIVcpz strains were significantly less pathogenic or non-pathogenic compared to HIV-1, manifesting lower degrees of CD4+ T-cell depletion and immune activation. Transcriptome analyses of CD4+ T cells from hu-BLT mice infected with SIVcpz versus HIV-1 revealed enhanced expression of genes related to cell survival and reduced inflammation/immune activation in SIVcpz-infected mice. Together, our study results demonstrate for the first time that SIVcpz is significantly less or non-pathogenic to human immune cells compared to HIV-1. Our findings lay the groundwork for a possible new understanding of the evolutionary origins of HIV-1, where the initial SIVcpz cross-species transmission virus may be initially less pathogenic to humans.

Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes.

HIV-1 arose as the result of spillover of simian immunodeficiency viruses (SIVs) from great apes in Africa, namely from chimpanzees and gorillas. Chimpanzees and gorillas were, themselves, infected with SIV after virus spillover from African monkeys. During spillover events, SIV is thought to require adaptation to the new host species. The host barriers that drive viral adaptation have predominantly been attributed to restriction factors, rather than cofactors (host proteins exploited to promote viral replication). Here, we consider the role of one cofactor, RanBP2, in providing a barrier that drove viral genome evolution during SIV spillover events. RanBP2 (also known as Nup358) is a component of the nuclear pore complex known to facilitate nuclear entry of HIV-1. Our data suggest that transmission of SIV from monkeys to chimpanzees, and then from chimpanzees to gorillas, both coincided with changes in the viral capsid that allowed interaction with RanBP2 of the new host species. However, human RanBP2 subsequently provided no barrier to the zoonotic transmission of SIV from chimpanzees or gorillas, indicating that chimpanzee- and gorilla-adapted SIVs are pre-adapted to humans in this regard. Our observations are in agreement with RanBP2 driving virus evolution during cross-species transmissions of SIV, particularly in the transmissions to and between great ape species.

Stably expressed APOBEC3H forms a barrier for cross-species transmission of simian immunodeficiency virus of chimpanzee to humans.

APOBEC3s (A3s) are potent restriction factors of human immunodeficiency virus type 1/simian immunodeficiency viruses (HIV-1/SIV), and can repress cross-species transmissions of lentiviruses. HIV-1 originated from a zoonotic infection of SIV of chimpanzee (SIVcpz) to humans. However, the impact of human A3s on the replication of SIVcpz remains unclear. By using novel SIVcpz reporter viruses, we identified that human APOBEC3B (A3B) and APOBEC3H (A3H) haplotype II strongly reduced the infectivity of SIVcpz, because both of them are resistant to SIVcpz Vifs. We further demonstrated that human A3H inhibited SIVcpz by deaminase dependent as well independent mechanisms. In addition, other stably expressed human A3H haplotypes and splice variants showed strong antiviral activity against SIVcpz. Moreover, most SIV and HIV lineage Vif proteins could degrade chimpanzee A3H, but no Vifs from SIVcpz and SIV of gorilla (SIVgor) lineages antagonized human A3H haplotype II. Expression of human A3H hapII in human T cells efficiently blocked the spreading replication of SIVcpz. The spreading replication of SIVcpz was also restricted by stable A3H in human PBMCs. Thus, we speculate that stably expressed human A3H protects humans against the cross-species transmission of SIVcpz and that SIVcpz spillover to humans may have started in individuals that harbor haplotypes of unstable A3H proteins.

Short Communication: Comparative Susceptibility of Rhesus Macaques of Indian and Chinese Origin to Vaginal Simian-Human Immunodeficiency Virus Transmission as Models for HIV Prevention Research.

Historically, Indian rhesus macaques (iRMs) have been preferred for simian immunodeficiency virus (SIV)/HIV prevention, pathogenesis, and treatment studies, yet their supply is limited. Chinese rhesus macaques (cRMs) are currently more available, yet little is known regarding the relative susceptibility of this subspecies to vaginal transmission of SIV or simian-human immunodeficiency virus (SHIV). In this study, we compared the susceptibility of 40 cRMs and 21 iRMs with a single vaginal challenge with SHIVsf162P. Our results showed that cRMs have comparable primary SHIV infection as iRMs, underscoring their equal importance in studies of HIV transmission and prevention.

Epigallocatechin Gallate Inhibits Macaque SEVI-Mediated Enhancement of SIV or SHIV Infection

Human semen contains a factor that can enhance HIV infection up to 10-fold in cultures. This factor is termed semen-derived enhancer of virus infection (SEVI) and is composed of proteolytic fragments (PAP248-286) from prostatic acid phosphatase in semen. In this study, we examined whether macaque SEVI can facilitate simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (SHIV) infection. We also studied the effect of epigallocatechin gallate (EGCG) on macaque SEVI-mediated SIV or SHIV enhancement. SIV or SHIV was mixed with different concentrations of macaque SEVI in the presence or absence of EGCG. The mixture was added to cultures of TZM-bl cells or macaque PBMCs. The effect of EGCG on macaque SEVI was measured by Congo-red staining assay and thioflavin T (ThT) fluorescence assay and was visualized by a transmission electron microscope. We identified that there is one amino acid difference at the site of 277 between human PAP248-286 and macaque PAP248-286. Macaque SEVI significantly enhanced SIV or SHIV infection of TZM-bl cells and macaque PBMCs. EGCG could block macaque SEVI-mediated enhancement of SIV or SHIV infection. Mechanistically, EGCG could degrade the formation of macaque SEVI amyloid fibrils that facilitates HIV attachment to the target cells. The finding that macaque SEVI could enhance SIV or SHIV infection indicates the possibility to use the macaque SEVI in vivo studies with the macaque models. In addition, future studies are necessary to examine whether EGCG can be used as an effective microbicide for preventing SIV or SHIV mucosal transmission.

Phyloepidemiological Analysis Reveals that Viral Divergence Led to the Paucity of Simian Immunodeficiency Virus SIVmus/gsn/mon Infections in Wild Populations.

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) is the result of cross-species transmission of simian immunodeficiency virus from chimpanzees (SIVcpz). SIVcpz is a chimeric virus which shares common ancestors with viruses infecting red-capped mangabeys and a subset of guenon species. The epidemiology of SIV infection in hominoids is characterized by low prevalences and an uneven geographic distribution. Surveys in Cameroon indicated that two closely related members of the guenon species subset, mustached guenons and greater spot-nosed guenons, infected with SIVmus and SIVgsn, respectively, also have low rates of SIV infections in their populations. Compared to that for other monkeys, including red-capped mangabeys and closely related guenon species, such an epidemiology is unusual. By intensifying sampling of geographically distinct populations of mustached and greater spot-nosed guenons in Gabon and including large sample sets of mona guenons from Cameroon, we add strong support to the hypothesis that the paucity of SIV infections in wild populations is a general feature of this monophyletic group of viruses. Furthermore, comparative phylogenetic analysis reveals that this phenotype is a feature of this group of viruses infecting phylogenetically disparate hosts, suggesting that this epidemiological phenotype results from infection with these HIV-1-related viruses rather than from a common host factor. Thus, these HIV-1-related viruses, i.e., SIVcpz and the guenon viruses which share an ancestor with part of the SIVcpz genome, have an epidemiology distinct from that found for SIVs in other African primate species.IMPORTANCE Stable virus-host relationships are established over multiple generations. The prevalence of viral infections in any given host is determined by various factors. Stable virus-host relationships of viruses that are able to cause persistent infections and exist with high incidences of infection are generally characterized by a lack of morbidity prior to host reproduction. Such is the case for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections of humans. SIV infections of most African primate species also satisfy these criteria, with these infections found at a high prevalence and with rare cases of clinical disease. In contrast, SIVcpz, the ancestor of HIV-1, has a different epidemiology, and it has been reported that infected animals suffer from an AIDS-like disease in the wild. Here we conclusively demonstrate that viruses which are closely related to SIVcpz and infect a subset of guenon monkeys show an epidemiology resembling that of SIVcpz.

A historical perspective: Simian AIDS-an accidental windfall.

For the past 30years, Simian AIDS has provided an indispensible animal model for the human disease. This historical perspective highlights the circumstances leading to the creation of this experimental model. Historical information and stored non-human primate (NHP) specimens, including isolates of Simian immunodeficiency virus (SIV), were analyzed by molecular epidemiologic methods to trace the lineage and transmission of SIV among NHPs at US primate centers. The rhesus and stump-tailed macaque models of Simian AIDS are the result of the accidental transmission of SIV from healthy sooty mangabey carriers to naïve macaques during the course of human kuru experimental transmission studies at UC Davis during the 1960s. Simian AIDS, first recognized in the 1980s, is the accidental result of experimental kuru transmission experiments carried out in the 1960s, which led to the discovery of infectious prions but inadvertently transmitted SIV, unknown at that time, from sooty mangabeys to macaques.

Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into the vpu genes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-κB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4+ T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques.

Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4(+) T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity. Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses.

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice.

Despite their antiviral effect, the invivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. Inexplants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3-4weeks. Similarly intravaginal application of type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation, and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission but systemic interferons do not.

Th17 Cells Are Preferentially Infected Very Early after Vaginal Transmission of SIV in Macaques.

The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque simian immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hr after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV-infected cells expressed the transcriptional regulator RORγt, confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17-lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission.

Down-modulation of primate lentiviral receptors by Nef proteins of simian immunodeficiency virus (SIV) of chimpanzees (SIVcpz) and related SIVs: implication for the evolutionary event at the emergence of SIVcpz.

It has been estimated that human immunodeficiency virus type 1 originated from the zoonotic transmission of simian immunodeficiency virus (SIV) of chimpanzees, SIVcpz, and that SIVcpz emerged by the recombination of two lineages of SIVs in Old World monkeys (SIVgsn/mon/mus in guenons and SIVrcm in red-capped mangabeys) and SIVcpz Nef is most closely related to SIVrcm Nef. These observations suggest that SIVrcm Nef had an advantage over SIVgsn/mon/mus during the evolution of SIVcpz in chimpanzees, although this advantage remains uncertain. Nef is a multifunctional protein which downregulates CD4 and coreceptor proteins from the surface of infected cells, presumably to limit superinfection. To assess the possibility that SIVrcm Nef was selected by its superior ability to downregulate viral entry receptors in chimpanzees, we compared its ability to down-modulate viral receptor proteins from humans, chimpanzees and red-capped mangabeys with Nef proteins from eight other different strains of SIVs. Surprisingly, the ability of SIVrcm Nef to downregulate CCR5, CCR2B and CXCR6 was comparable to or lower than SIVgsn/mon/mus Nef, indicating that ability to down-modulate chemokine receptors was not the selective pressure. However, SIVrcm Nef significantly downregulates chimpanzee CD4 over SIVgsn/mon/mus Nefs. Our findings suggest the possibility that the selection of SIVrcm Nef by ancestral SIVcpz is due to its superior capacity to down-modulate chimpanzees CD4 rather than coreceptor proteins.

Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection.

α4β7 integrin expressing CD4+ T cells preferentially traffic to gut-associated lymphoid tissues (GALT) and play a key role in HIV/SIV pathogenesis. The administration of an anti-α4β7 monoclonal antibody during acute infection protects macaques from transmission following repeated low-dose intra-vaginal challenges with SIVmac251. In treated animals that became infected the GALT was significantly protected and CD4+ T–cell numbers were maintained. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.

Nonhuman primate models for cell-associated simian immunodeficiency virus transmission: the need to better understand the complexity of HIV mucosal transmission.

Nonhuman primates are extensively used to assess strategies to prevent infection from sexual exposure to human immunodeficiency virus (HIV) and to study mechanisms of mucosal transmission. However, although semen represents one of the most important vehicles for the virus, the vast majority of preclinical challenge studies have used cell-free simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV) viral particles inoculated as diluted culture supernatants. Semen is a complex body fluid containing many factors that may facilitate or decrease HIV infectiousness. The virus in semen is present in different forms: as free virus particles or as cell-associated virus (ie, within infected leukocytes). Although cell-to-cell transmission of HIV is highly efficient, the role of cell-associated virus in semen has been surprisingly poorly investigated in nonhuman primate models. Mucosal exposure of macaques to cell-associated SIV by using infected peripheral blood mononuclear cells or spleen cells has been shown to be an efficient means of infection; however, it has yet to be shown that SIV- or SHIV-infected seminal leukocytes can transmit infection in vivo. Improvement of animal models to better recapitulate the complex microenvironment at portals of HIV entry is needed for testing candidate antiretrovirals, microbicides, and vaccines.