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Nonhuman primate (NHP) models employing simian/simian-human immunodeficiency viruses (SIV/SHIVs) played a major role in the study of HIV pathogenesis, latency, and cure studies in a preclinical setting. However, it took many years to arrive at the current effective triple drug ARV regimen against SIV due to the genetic differences with that of HIVs. Since new combinations of drugs will be used in the evolving HIV cure studies, a small animal model would be ideal to determine their efficacy against the commonly used SIVs such as SIVmac239 to triage ineffective drugs prior to their application in NHPs. We recently determined that humanized mice (hu-mice) with a transplanted human immune system are permissive to SIVmac strains in addition to HIVs. Based on this novel finding, here we evaluated the utility of this dual-purpose hu-mouse model to test different ART regimens against SIVmac239. Infected mice showing chronic viremia were treated with a combination anti-retroviral treatment (cART) regimen consisting of emtricitabine/elvitegravir/tenofovir disoproxil fumarate (FTC/EVG/TDF). Full viral suppression was seen for several weeks in SIVmac239-infected and treated mice similar to that seen with HIV-1 BaL virus used as a control. However, viral rebound was eventually observed in SIVmac239 infected mice during the treatment period, suggesting viral escape compared to HIV-1 BaL with which viral suppression was fully sustained. Next, a cART regimen consisting of emtricitabine/bictegravir/tenofovir alafenamide fumarate (FTC/BIC/TAF) was similarly evaluated. Our results showed that this ARV regimen was fully effective in rapidly suppressing both SIVmac239 and HIV-1 BaL. Complete viral suppression was maintained until treatment interruption after which viral loads rebounded. These findings highlight the utility of humanized mice for in vivo screening of new combinations of ARV compounds against various SIVs prior to employing them in NHPs. In addition to identifying new effective cART regimens against SIVs, this model would also be amenable to evaluating immunotherapeutic strategies using broadly neutralizing antibodies, LRAs and novel therapeutics in comparative cure studies of SIV and HIV.

In this study, we demonstrate, for the first time, that the natural, non-pathogenic SIV infection of the African monkey SM has a clinical impact which is revealed in terms of main causes of mortality, which are significantly different in the infected animals as compared to the uninfected ones. Indeed, SIV-infected SMs are at higher risk of dying of infectious diseases but appear to be somewhat protected from cardiovascular causes of death. The identification of a specific pattern of mortality associated with the infection suggests that the host-pathogen interaction between SIV and the SM immune system, while non-pathogenic in nature, has a detectable impact on the overall health status of the animals.

A significant challenge to HIV eradication is the elimination of viral reservoirs in germinal center (GC) T follicular helper (Tfh) cells. However, GCs are considered to be immune privileged for antiviral CD8 T cells. Here, we show a population of simian immunodeficiency virus (SIV)-specific CD8 T cells express CXCR5 (C-X-C chemokine receptor type 5, a chemokine receptor required for homing to GCs) and expand in lymph nodes (LNs) following pathogenic SIV infection in a cohort of vaccinated macaques. This expansion was greater in animals that exhibited superior control of SIV. The CXCR5+ SIV-specific CD8 T cells demonstrated enhanced polyfunctionality, restricted expansion of antigen-pulsed Tfh cells in vitro, and possessed a unique gene expression pattern related to Tfh and Th2 cells. The increase in CXCR5+ CD8 T cells was associated with the presence of higher frequencies of SIV-specific CD8 T cells in the GC. Following TCR-driven stimulation in vitro, CXCR5+ but not CXCR5− CD8 T cells generated both CXCR5+ aswell as CXCR5− cells. However, the addition of TGF-β to CXCR5− CD8 T cells induced a population of CXCR5+ CD8 T cells, suggesting that this cytokine may be important in modulating these CXCR5+ CD8 T cells in vivo. Thus, CXCR5+ CD8 T cells represent a unique subset of antiviral CD8 T cells that expand in LNs during chronic SIV infection and may play a significant role in the control of pathogenic SIV infection.

Abstract Cell-free and cell-associated human immunodeficiency virus (HIV) may differently affect the immune system and the efficacy of prevention strategies. Here we examined mucosal events in simian immunodeficiency virus (SIV) infection, using infected cells together with cell-free virus and cell-free virus alone. Intravenously inoculated SIV-infected cells disseminated virus to the intestine within 16 hours. Infection with both virus forms accelerated viral dissemination in the intestinal mucosa and the loss of mucosal CD4+ T cells as compared to infection with cell-free virus only. As all natural sources of HIV infection contain both virus forms, future prevention studies should focus on efficacy against both cell-free and cell-associated virus. Infection with a mixture of cell-free and cell-associated simian immunodeficiency virus (SIV) accelerated viral dissemination and CD4+ T-cell depletion in the intestine as compared to infection with cell-free SIV alone. Consequently, a mixture of both virus forms should be used in treatment models.

T follicular helper CD4 cells (Tfh) are essential for the development and maintenance of germinal center (GC) reactions, a critical process that promotes the generation of long-lived high affinity humoral immunity. It is becoming increasingly evident that GC-Tfh cells are heterogeneous in nature with some cellular characteristics associated with a Th1, Th2, and Th17 phenotype. Emerging studies suggest that GC-Tfh cells are directed to differentiate into distinct phenotypes during chronic HIV/SIV infection and these changes in GC-Tfh cells can greatly impact the B cell response and subclass of antibodies generated. Studies in HIV-infected humans have shown that certain Tfh phenotypes are associated with the generation of broadly neutralizing antibody responses. Moreover, the susceptibility of particular GC-Tfh subsets to HIV infection within the secondary lymphoid sites can also impact GC-Tfh/B cell interactions. In this review, we discuss the recent advances that show Tfh heterogeneity during chronic HIV/SIV infection. In particular, we will discuss the dynamics of GC-Tfh cells, their altered differentiation state and function, and their impact on B cell responses during HIV/SIV infection. In addition, we will also discuss the potential role of a recently described novel subset of follicular homing CXCR5 CD8 T cells (Tfc) and their importance in contributing to control of chronic HIV/SIV infection. A better understanding of the mechanistic role of follicular homing CD4 and CD8 T cells during HIV/SIV infection will aid in the design of vaccines and therapeutic strategies to prevent and treat HIV/AIDS.

Simian immunodeficiency virus (SIV) vaccines based upon 68-1 Rhesus Cytomegalovirus (RhCMV) vectors show remarkable protection against pathogenic SIVmac239 challenge. Across multiple independent rhesus macaque (RM) challenge studies, nearly 60% of vaccinated RM show early, complete arrest of SIVmac239 replication after effective challenge, whereas the remainder show progressive infection similar to controls. Here, we performed viral sequencing to determine whether the failure to control viral replication in non-protected RMs is associated with the acquisition of viral escape mutations. While low level viral mutations accumulated in all animals by 28 days-post-challenge, which is after the establishment of viral control in protected animals, the dominant circulating virus in virtually all unprotected RMs was nearly identical to the challenge stock, and there was no difference in mutation patterns between this cohort and unvaccinated controls. These data definitively demonstrate that viral mutation does not explain lack of viral control in RMs not protected by RhCMV/SIV vaccination. We further demonstrate that during chronic infection RhCMV/SIV vaccinated RMs do not acquire escape mutation in epitopes targeted by RhCMV/SIV, but instead display mutation in canonical MHC-Ia epitopes similar to unvaccinated RMs. This suggests that after the initial failure of viral control, unconventional T cell responses induced by 68-1 RhCMV/SIV vaccination do not exert strong selective pressure on systemically replicating SIV.

Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques. Nef-positive EVs were functional, i.e., capable of membrane fusion and depositing their content into recipient cells. The EVs were able to transfer Nef into recipient cells. This suggests that Nef readily enters the exosome biogenesis pathway, whereas HIV virions are assembled at the plasma membrane. It suggests a novel mechanism by which lentiviruses can influence uninfected and uninfectable, i.e., CD4-negative, cells. IMPORTANCE Extracellular vesicles (EVs) transfer biologically active materials from one cell to another, either within the adjacent microenvironment or further removed. EVs also package viral RNAs, microRNAs, and proteins, which contributes to the pathophysiology of infection. In this report, we show that both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) incorporate the virus-encoded Nef protein into EVs, including EVs circulating in the blood of SIV-infected macaques and that this presents a novel mechanism of Nef transfer to naive and even otherwise non-infectable cells. Nef is dispensable for viral replication but essential for AIDS progression in vivo . Demonstrating that Nef incorporation into EVs is conserved across species implicates EVs as novel mediators of the pathophysiology of HIV. It could help explain the biological effects that HIV has on CD4-negative cells and EVs could become biomarkers of disease progression. Extracellular vesicles (EVs) transfer biologically active materials from one cell to another, either within the adjacent microenvironment or further removed. EVs also package viral RNAs, microRNAs, and proteins, which contributes to the pathophysiology of infection. In this report, we show that both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) incorporate the virus-encoded Nef protein into EVs, including EVs circulating in the blood of SIV-infected macaques and that this presents a novel mechanism of Nef transfer to naive and even otherwise non-infectable cells. Nef is dispensable for viral replication but essential for AIDS progression in vivo . Demonstrating that Nef incorporation into EVs is conserved across species implicates EVs as novel mediators of the pathophysiology of HIV. It could help explain the biological effects that HIV has on CD4-negative cells and EVs could become biomarkers of disease progression.

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4⁺ T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the “leaky gut,” which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4⁺ T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid β-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.

Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after antiretrovial therapy (ART) interruption (ATI) by treating SIV-infected and ART-suppressed macaques with either an anti-PD-1 antibody (n = 7) or saline (n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIV-specific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100- to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research.