HIV Pathogenesis Research Articles

Defective HIV proviruses: possible involvement in the HIV infection pathogenesis

This review article analyzes information obtained from a literature search on defective HIV genomes (HIV-1, Human Immunodeficiency Virus, Lentivirus, Orthoretrovirinae, Retroviridae). It discusses the origins of defective HIV genomes, their potential for transcription and translation, and the role of defective RNA and proteins in stimulating both innate and adaptive immunity. The article also explores their contribution to HIV pathogenesis, immune system hyperactivation despite successful antiretroviral therapy (ART), and the evolutionary processes in HIV proviral populations under ART. Additionally, it addresses challenges in reservoir elimination and HIV eradication that arise from the existence of defective HIV viruses.

A dual-purpose humanized mouse model for testing antiviral strategies against both SIV and HIV

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.

HIV disease progression among heterosexually-infected individuals before the introduction of universal ART in China: A linear mixed-effects model.

In 2016, China introduced universal antiretroviral therapy (ART) for all HIV-infected individuals regardless of CD4 cell count. However, the natural history and rate of CD4 count decline among heterosexually-infected individuals remain uncharacterized. Analyzing national surveillance data can address this gap and shed light on the pathogenesis of HIV in this population. We used a linear mixed-effects model to assess CD4 trajectory over time before ART initiation and estimated the median time from HIV seroconversion to reaching CD4 thresholds of < 500, < 350, and < 200 cell/mm3. From the Chinese HIV/AIDS Comprehensive Response Information Management System, 59,085 eligible individuals were identified, with 113 having data to estimate the date of HIV seroconversion. The linear mixed-effects models estimated an intercept of 23.64 (95% confidence interval [CI]: 22.41 to 24.87) and a slope of -1.32 (95% CI: -1.34 to -1.30) for males, and an intercept of 22.70 (95% CI: 21.00 to 24.40) and a slope of -1.29 (95% CI: -1.31 to -1.27) for females. The estimated median times from HIV seroconversion to reaching CD4 count thresholds of < 500, < 350, < 200 cells/mm3 were 0.97, 3.74, and 7.20 years for males, and 0.26, 3.09, and 6.48 years for females, respectively. Males consistently took longer to reach these CD4 count thresholds compared to females of the same age group. Older individuals (≥ 40 years) reached CD4 thresholds faster than younger individuals (15-29 years), indicating more rapid disease progression in older people living with HIV.

Phenotypic Characterization of Subtype A and Recombinant AC Transmitted/Founder Viruses from a Rwandan HIV-1 Heterosexual Transmission Cohort

HIV-1 subtypes have distinct geographical distributions, with subtypes A, C, and D and inter-subtype recombinants circulating in sub-Saharan Africa. Historically, individuals living with subtype A viruses exhibit slower CD4 decline and progression to AIDS diagnosis. Despite this, there are few authentic infectious molecular clones (IMCs) of subtype A or AC recombinant transmitted founder (TF) viruses with which to investigate viral impacts on pathogenesis. In this study, we constructed 16 authentic subtype A1 and 4 A1C recombinant IMCs from the IAVI Rwandan Protocol C acute infection cohort and characterized these viruses phenotypically. The virus replicative capacity (RC) scores varied over 50-fold, but the natural substitution of non-consensus amino acids in the p17(MA) domain of Gag was generally linked to higher RC levels. Sensitivity to a panel of broadly neutralizing antibodies (bNAbs) showed that all but one TF was sensitive to N6, which targets the CD4 binding site, while bNAbs PG16 and PGT 128 had a similar level of potency but reduced breadth against our panel of viruses. In contrast, bNAb 10E8V4 revealed high breadth but much lower potency. This panel of well-characterized, authentic subtype A and AC recombinant IMCs provides a resource for studies on the role of the virus subtype in HIV-1 transmission, pathogenesis, and vaccine design.

Death and survival of gut CD4 T cells following HIV-1 infection ex vivo

Abstract The gastrointestinal (GI) tract is ground zero for the massive and sustained CD4 T cell depletion during acute HIV-1 infection. To date, the molecular mechanisms governing this fundamental pathogenic process remain unclear. HIV-1 infection in the GI tract is associated with chronic inflammation due to a disrupted epithelial barrier that results in microbial translocation. Here, we utilized the Lamina Propria Aggregate Culture model to demonstrate that the profound induction of Granzyme B (GZB) by bacteria in primary gut CD4 T cells ex vivo significantly contributes to HIV-1-mediated CD4 T cell death. Counterintuitively, a substantial fraction of gut GZB+ CD4 T cells harboring high levels of HIV-1 infection survive via a pathway linked to CD120b/TNFR2. Our findings underscore novel mechanisms governing the death and survival of gut CD4 T cells during HIV-1 infection that could inform strategies to counter HIV-1 pathogenesis and persistence in this critical tissue compartment.

Human genital dendritic cell heterogeneity confers differential rapid response to HIV-1 exposure

Dendritic cells (DCs) play critical roles in HIV pathogenesis and require further investigation in the female genital tract, a main portal of entry for HIV infection. Here we characterized genital DC populations at the single cell level and how DC subsets respond to HIV immediately following exposure. We found that the genital CD11c+HLA-DR+ myeloid population contains three DC subsets (CD1c+ DC2s, CD14+ monocyte-derived DCs and CD14+CD1c+ DC3s) and two monocyte/macrophage populations with distinct functional and phenotypic properties during homeostasis. Following HIV exposure, the antiviral response was dominated by DCs’ rapid secretory response, activation of non-classical inflammatory pathways and host restriction factors. Further, we uncovered subset-specific differences in anti-HIV responses. CD14+ DCs were the main population activated by HIV and mediated the secretory antimicrobial response, while CD1c+ DC2s activated inflammasome pathways and IFN responses. Identification of subset-specific responses to HIV immediately after exposure could aid targeted strategies to prevent HIV infection.

Alterations of the gut microbiome in HIV infection highlight human anelloviruses as potential predictors of immune recovery

BackgroundHIV-1 infection is characterized by a massive depletion of mucosal CD4 T cells that triggers a cascade of events ultimately linking gut microbial dysbiosis to HIV-1 disease progression and pathogenesis. The association between HIV infection and the enteric virome composition is less characterized, although viruses are an essential component of the gut ecosystem. Here, we performed a cross-sectional analysis of the fecal viral (eukaryotic viruses and bacteriophages) and bacterial microbiome in people with HIV (PWH) and in HIV-negative individuals. To gain further insight into the association between the gut microbiome composition, HIV-associated immunodeficiency, and immune recovery, we carried out a longitudinal study including 14 PWH who initiated antiretroviral therapy (ART) and were followed for 24 months with samplings performed at baseline (before ART) and at 2, 6, 12, and 24 months post-ART initiation.ResultsOur data revealed a striking expansion in the abundance and prevalence of several human virus genomic sequences (Anelloviridae, Adenoviridae, and Papillomaviridae) in stool samples of PWH with severe immunodeficiency (CD4 < 200). We also noted a decreased abundance of sequences belonging to two plant viruses from the Tobamovirus genus, a reduction in bacterial alpha diversity, and a decrease in Inoviridae bacteriophage sequences. Short-term ART (24 months) was linked to a significant decrease in human Anelloviridae sequences. Remarkably, the detection of Anellovirus sequences at baseline independently predicted poor immune recovery, as did low CD4 T cell counts. The bacterial and bacteriophage populations were unique to each PWH with individualized trajectories; we found no discernable pattern of clustering after 24 months on ART.ConclusionAdvanced HIV-1 infection was associated with marked alterations in the virome composition, in particular a remarkable expansion of human anelloviruses, with a gradual restoration after ART initiation. In addition to CD4 T cell counts, anellovirus sequence detection might be useful to predict and monitor immune recovery. This study confirms data on the bacteriome and expands our knowledge on the viral component of the gut microbiome in HIV-1 infection.3oR8qDfXoWY9s_P5ES648YVideo

Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors.

Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4+ Tcell counts despite uncontrolled viral replication-a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies. We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors. Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4+ Tcell apoptosis. In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis. The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).

Pathogenesis of HIV associated nephropathy in children and adolescents: taking a hard look 40 years later in the era of gene-environmental interaction.

HIV-associated nephropathy (HIVAN) is a kidney disease that affects mainly people of African ancestry with a high HIV-1 viral load. New antiretroviral therapies (ART) have been highly efficient preventing and improving the outcome of HIVAN. However, providing chronic ART to children and adolescents living with HIV (CALWH) remains a significant challenge all over the world. More that 2.5 million CALWH, including those living in Sub-Saharan Africa, continue to be at high risk of developing HIVAN. Much of our understanding of the pathogenesis of HIVAN is based on studies conducted in transgenic mice and adults with HIVAN. However, CALWH may experience different health outcomes, risk factors, and susceptibilities to HIVAN in comparison to adults. This article reviews the progress made over the last 40 years in understanding the pathogenesis of HIVAN in CALWH, focusing on how the HIV virus, alongside genetic and environmental factors, contributes to the development of this disease. The landmark discovery that two risks alleles of the Apolipoprotein-1 (APOL1) gene play a critical role in HIVAN has significantly advanced our understanding of the disease's pathogenesis. However, we still need to understand why renal inflammation persists despite ART and determine whether the kidney may harbor HIV reservoirs that need to be eliminated to cure HIV permanently. For these reasons, we emphasize reviewing how HIV-1 infects renal cells, affects their growth and regeneration, and discussing how inflammatory cytokines and APOL1 affect the outcome of childhood HIVAN.

Effect of fentanyl on HIV expression in peripheral blood mononuclear cells.

Illicit drug use, particularly the synthetic opioid fentanyl, presents a significant global health challenge. Previous studies have shown that fentanyl enhances viral replication; yet, the mechanisms by which it affects HIV pathogenesis remain unclear. This study investigated the impact of fentanyl on HIV replication in CD4+ T lymphocytes. CD4+ T lymphocytes from HIV-negative donors were activated, infected with HIVNL4-3, and treated with fentanyl. HIV proviral DNA and p24 antigen expression were quantified using real-time PCR and ELISA, respectively. Single-cell RNA libraries were analyzed to identify differentially expressed genes. Results indicated that fentanyl treatment increased HIV p24 expression and proviral DNA levels, and naltrexone mitigated these effects. Single-cell RNAseq analysis identified significantly altered gene expression in CD4+ T lymphocytes. The results of our findings suggest that fentanyl promotes HIV replication ex vivo, emphasizing the need for a deeper understanding of opioid-virus interactions to develop better treatment strategies for individuals with HIV and opioid use disorder.

The role of heat shock proteins in HIV-1 pathogenesis: a systematic review investigating HSPs-HIV-1 correlations and interactions.

The human immunodeficiency virus (HIV) pandemic is a global health emergency. Studies suggest a connection between heat shock proteins (HSPs) and HIV-1 infection pathogenesis. This systematic review aims to summarize HSPs' role in HIV-1 infection pathogenesis. A systematic literature search was undertaken across the National Library of Medicine (MEDLINE-PubMed), Science Direct, Web of Science, Scopus, SpringerLink, Sage, ProQuest, and Google Scholar databases, using related keywords to synthesize the HSPs' role in HIV-1 infection pathogenesis. This literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in the Open Science Framework (OSF) database under DOI 10.17605/OSF.IO/VK3DJ. A database search revealed 3,332 articles, with 14 in vitro studies analysing the interaction between HSPs and HIV-1 across different cell types. HSPs are involved in HIV-1 infection through direct interactions and indirect responses to cellular stress, including HSP40, HSP70, HSPBP1, and HSP90. The study explores HSP interactions at various stages of the viral life cycle, including entry, uncoating, replication, transmission, and latency reactivation. HSPs are crucial for the HIV lifecycle and immune response, offering the potential for new therapeutic strategies. Further research is needed to understand the clinical significance and target potential.

The impact of sex on HIV immunopathogenesis and therapeutic interventions.

Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.

HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration.

HIV-1 integration favors nuclear speckle (NS)-proximal chromatin and viral infection induces the formation of capsid-dependent CPSF6 condensates that colocalize with nuclear speckles (NSs). Although CPSF6 displays liquid-liquid phase separation (LLPS) activity in vitro, the contributions of its different intrinsically disordered regions, which includes a central prion-like domain (PrLD) with capsid binding FG motif and C-terminal mixed-charge domain (MCD), to LLPS activity and to HIV-1 infection remain unclear. Herein, we determined that the PrLD and MCD both contribute to CPSF6 LLPS activity in vitro. Akin to FG mutant CPSF6, infection of cells expressing MCD-deleted CPSF6 uncharacteristically arrested at the nuclear rim. While heterologous MCDs effectively substituted for CPSF6 MCD function during HIV-1 infection, Arg-Ser domains from related SR proteins were largely ineffective. While MCD-deleted and wildtype CPSF6 proteins displayed similar capsid binding affinities, the MCD imparted LLPS-dependent higher-order binding and co-aggregation with capsids in vitro and in cellulo. NS depletion reduced CPSF6 puncta formation without significantly affecting integration into NS-proximal chromatin, and appending the MCD onto a heterologous capsid binding protein partially restored virus nuclear penetration and integration targeting in CPSF6 knockout cells. We conclude that MCD-dependent CPSF6 condensation with capsids underlies post-nuclear incursion for viral DNA integration and HIV-1 pathogenesis.

The Role of Tumor Suppressor p53 Protein in HIV-Host Cell Interactions.

The virus-host relationship is indispensable for executing successful viral infection. The pathogenesis of HIV is determined by an intricate interaction between the host and the virus for the regulation of HIV infection, thereby influencing various aspects, including the regulation of signaling pathways. High mutation rates and population heterogeneity characterize HIV with consequences for viral pathogenesis and the potential to escape the immune system and anti-viral inhibitors used in therapy. The origin of the high mutation rates exhibited by HIV may be attributed to a limited template-copied fidelity that likely operates in the cytoplasm. HIV-1 infection induces upregulation and activation of tumor suppressor p53 protein in the early stages of HIV-1 infection. p53 plays a multifaceted role in the context of HIV infection, thereby affecting viral replication. p53 is involved in maintaining genetic integrity, actively participating in various DNA repair processes through its various biochemical activities and via its ability to interact with components of the repair machinery. This report focuses on the impact of the p53 protein on the HIV-1 reverse transcription process while incorporating various incorrect and non-canonical nucleotides. The presence of functional host-coded p53 protein with proofreading-repair activities in the cytoplasm may lead to various biological outcomes.

HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43

Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1.

Follicular Immune Landscaping Reveals a Distinct Profile of FOXP3hiCD4hi T Cells in Treated Compared to Untreated HIV.

Follicular helper CD4hi T cells (TFH) are a major cellular pool for the maintenance of the HIV reservoir. Therefore, the delineation of the follicular (F)/germinal center (GC) immune landscape will significantly advance our understanding of HIV pathogenesis. We have applied multiplex confocal imaging, in combination with the relevant computational tools, to investigate F/GC in situ immune dynamics in viremic (vir-HIV), antiretroviral-treated (cART HIV) People Living With HIV (PLWH) and compare them to reactive, non-infected controls. Lymph nodes (LNs) from viremic and cART PLWH could be further grouped based on their TFH cell densities in high-TFH and low-TFH subgroups. These subgroups were also characterized by different in situ distributions of PD1hi TFH cells. Furthermore, a significant accumulation of follicular FOXP3hiCD4hi T cells, which were characterized by a low scattering in situ distribution profile and strongly correlated with the cell density of CD8hi T cells, was found in the cART-HIV low-TFH group. An inverse correlation between plasma viral load and LN GrzBhiCD8hi T and CD16hiCD15lo cells was found. Our data reveal the complex GC immune landscaping in HIV infection and suggest that follicular FOXP3hiCD4hi T cells could be negative regulators of TFH cell prevalence in cART-HIV.

Elevated stress-responsive biomarkers are associated with HIV acquisition in young women in rural South Africa: A HPTN 068 case cohort study.

Biological markers of stress have been associated with HIV progression and pathogenesis but not with HIV incidence. We sought to determine if elevated stress-responsive biomarkers would be associated with incident HIV among adolescent girls and young women (AGYW). We conducted a case-cohort study within the HIV Prevention Trials Network (HPTN) 068 study among 949 AGYW in South Africa. Cases were AGYW who tested HIV-positive during the eight-year follow-up. Unmatched controls were randomly selected from the HIV-negative population at enrollment. Dried blood spots from cases and controls were tested from enrollment (2011-2012) for C-reactive protein (CRP), herpes simplex virus type-1 (HSV-1) antibody titers, and cytomegalovirus (CMV) antibody titers. Cox proportional hazards models estimated the association between each biomarker and time to incident HIV. Compared to AGYW with the lowest CRP levels, those with medium and high CRP levels had a higher hazard ratio (HR) of incident HIV (HR: 1.45, 95% CI: 0.95, 2.21; HR: 1.50, 95% CI: 0.98,2.30, respectively), although not statistically significant. The relative hazard of incident HIV was also higher among AGYW who were CMV seropositive vs. seronegative (low antibodies HR: 2.18, 95% CI: 1.2,3.87; medium HR: 2.25, 95% CI: 1.28,3.95; high HR: 1.78, 95% CI: 0.99,3.21). Those with the highest HSV-1 antibody levels experienced an increased hazard of HIV compared to those who were HSV-1 seronegative (HR: 1.58, 95% CI: 1.03,2.44). Biological stress may increase AGYW's susceptibility to HIV acquisition through changes in immune function, viral infection, and increased biological vulnerability to disease.

Chronic HIV Infection Increases Monocyte NLRP3 Inflammasome-Dependent IL-1α and IL-1β Release.

Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1β, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

From dysbiosis to defense: harnessing the gut microbiome in HIV/SIV therapy

BackgroundAlthough the microbiota has been extensively associated with HIV pathogenesis, the majority of studies, particularly those using omics techniques, are largely correlative and serve primarily as a basis for hypothesis generation. Furthermore, most have focused on characterizing the taxonomic composition of the bacterial component, often overlooking other levels of the microbiome. The intricate mechanisms by which the microbiota influences immune responses to HIV are still poorly understood. Interventional studies on gut microbiota provide a powerful tool to test the hypothesis of whether we can harness the microbiota to improve health outcomes in people with HIV.ResultsHere, we review the multifaceted role of the gut microbiome in HIV/SIV disease progression and its potential as a therapeutic target. We explore the complex interplay between gut microbial dysbiosis and systemic inflammation, highlighting the potential for microbiome-based therapeutics to open new avenues in HIV management. These include exploring the efficacy of probiotics, prebiotics, fecal microbiota transplantation, and targeted dietary modifications. We also address the challenges inherent in this research area, such as the difficulty in inducing long-lasting microbiome alterations and the complexities of study designs, including variations in probiotic strains, donor selection for FMT, antibiotic conditioning regimens, and the hurdles in translating findings into clinical practice. Finally, we speculate on future directions for this rapidly evolving field, emphasizing the need for a more granular understanding of microbiome-immune interactions, the development of personalized microbiome-based therapies, and the application of novel technologies to identify potential therapeutic agents.ConclusionsOur review underscores the importance of the gut microbiome in HIV/SIV disease and its potential as a target for innovative therapeutic strategies.

Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection.

Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.