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A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated (“putative progressors”, PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = −0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia. [ABSTRACT FROM AUTHOR]

Introduction: This study used an unsupervised machine learning algorithm, sidClustering and random forests, to identify clusters of risk behaviors of Bacterial Vaginosis (BV), the most common cause of abnormal vaginal discharge linked to STI and HIV acquisition. Methods: Participants were 391 cisgender women in Miami, Florida, with a mean of 30.8 (SD = 7.81) years of age; 41.7% identified as Hispanic; 41.7% as Black and 44.8% as White. Participants completed measures of demographics, risk behaviors [sexual, medical, and reproductive history, substance use, and intravaginal practices (IVP)], and underwent collection of vaginal samples; 135 behavioral variables were analyzed. BV was diagnosed using Nugent criteria. Results: We identified four clusters, and variables were ranked by importance in distinguishing clusters: Cluster 1: nulliparous women who engaged in IVPs to clean themselves and please sexual partners, and used substances frequently [n = 118 (30.2%)]; Cluster 2: primiparous women who engaged in IVPs using vaginal douches to clean themselves (n = 112 (28.6%)]; Cluster 3: primiparous women who did not use IVPs or substances [n = 87 (22.3%)]; and Cluster 4: nulliparous women who did not use IVPs but used substances [n = 74 (18.9%)]. Clusters were related to BV (p < 0.001). Cluster 2, the cluster of women who used vaginal douches as IVPs, had the highest prevalence of BV (52.7%). Conclusions: Machine learning methods may be particularly useful in identifying specific clusters of high-risk behaviors, in developing interventions intended to reduce BV and IVP, and ultimately in reducing the risk of HIV infection among women. [ABSTRACT FROM AUTHOR]

Background: Miami, Florida is an epicenter of the HIV epidemic in the US, with 20% of new HIV infections occurring in women. Despite effectiveness of Pre-Exposure Prophylaxis (PrEP) in preventing HIV, only 10% of eligible women benefit from its use. Setting: This study evaluates PrEP awareness and use, and factors associated with PrEP awareness among sexually active women in Miami, Florida. Methods: Results reported in this study included cross-sectional data that were collected as part of a baseline visit from a parent study. Cis-gender, HIV-negative, 18-45-year-old, sexually active women were recruited as part of a study evaluating recurrent bacterial vaginosis and HIV risk. Participants completed questionnaires assessing socio-demographics, HIV risk factors, prior history of HIV testing and reproductive tract infections, PrEP awareness and use. Relationships between variables and PrEP awareness were analyzed and multivariable logistic regression identified variables strongly associated with PrEP awareness. Results: Among the 295 women enrolled, median age was 31 (24–38) years, 49% Black, 39% White, and 34% Hispanic. Of 63% who knew about PrEP, only 5% were on PrEP. Women with income below poverty line (OR = 2.00[1.04,3.87];p = 0.04), more male sexual partners in past month (OR = 1.30[1.01,1.68];p = 0.04), lifetime HIV testing (OR = 6.42[2.83,14.52];p<0.01), and current bacterial vaginosis (OR = 2.28[1.18,4.40];p = 0.01) were more likely to be aware of PrEP. Lower odds of PrEP awareness were associated with being Black (OR = 0.38[0.15,0.96];p = 0.04), Hispanic (OR = 0.18[0.08,0.39];p<0.01), heterosexual (OR = 0.29[0.11,0.77];p<0.01), and reporting inconsistent condom use during vaginal sex (OR = 0.21[0.08,0.56];p<0.01). Conclusion: PrEP awareness is low among reproductive age women in a high-risk setting. Culturally tailored interventions are needed to increase PrEP awareness and uptake, especially among Black and Hispanic women with inconsistent condom use during vaginal sex with male partners. [ABSTRACT FROM AUTHOR]

HIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections. [ABSTRACT FROM AUTHOR]

Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1LAI virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women. Author summary: HIV prevention strategies with antiretroviral drugs as pre-exposure prophylactics (PrEP) are not efficacious in women, in part due to biological factors such as the vaginal microbiome. Lactobacillus spp. prevent the colonization of dysbiotic bacteria (i.e. bacterial vaginosis), which is associated with increased HIV transmission. However, the role these microbes play in altering the pharmacokinetics of PrEP drugs is currently unknown. Here we show that primary bacteria from women with dysbiosis impact PrEP drug levels and kinetics. We found that dysbiotic microbes metabolize PrEP drugs faster than target cell uptake, and significantly alter HIV infection rates in vitro, and this can be predicted with novel computational modeling. Our results demonstrate that the vaginal microbiome may play a key role in HIV prevention through altering therapeutic drug levels via metabolism. Thus, better measurements and interventions for vaginal dysbiosis will be critical in improving the efficacy of HIV prevention efforts in women. [ABSTRACT FROM AUTHOR]

Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus in vitro or in vivo. Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5+ and CCR6+ CD4+ T cells in mucosal tissues, decreases in CD4+ T cells producing Th17 cell-associated cytokines, CD8+ T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]

An altered intestinal microbiome during chronic human immunodeficiency virus (HIV) infection is associated with mucosal dysfunction, inflammation, and disease progression. We performed a preclinical evaluation of the safety and efficacy of fecal microbiota transplantation (FMT) as a potential therapeutic in HIV-infected individuals. Antiretroviral-treated, chronically simian immunodeficiency virus (SIV)-infected rhesus macaques received antibiotics followed by FMT. The greatest microbiota shift was observed after antibiotic treatment. The bacterial community composition at 2 weeks post-FMT resembled the pre-FMT community structure, although differences in the abundances of minor bacterial populations remained. Immunologically, we observed significant increases in the number of peripheral Th17 and Th22 cells and reduced CD4+ T cell activation in gastrointestinal tissues post-FMT. Importantly, the transplant was well tolerated with no negative clinical side effects. Although this pilot study did not control for the differential contributions of antibiotic treatment and FMT to the observed results, the data suggest that FMT may have beneficial effects that should be further evaluated in larger studies. [ABSTRACT FROM AUTHOR]

HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-β, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear. [ABSTRACT FROM AUTHOR]

Women and girls represent a key population driving new HIV infections and persistence of the HIV pandemic. A key determinant of HIV susceptibility is the composition of the vaginal microbiome, which can influence the local immune cell population, inflammation status, and HIV prevention drug levels. While a low-diversity composition dominated by Lactobacillus crispatus is associated with a decreased risk of HIV acquisition, high diversity environments associated with bacterial vaginosis increase risk of HIV. Given the important role of the vaginal microbiome in determining HIV susceptibility, altering the microbiome towards a Lactobacillus -dominated state is an attractive complementary strategy to reduce HIV incidence rates. Here, we provide an overview of the mechanisms by which the vaginal microbiome may contribute to HIV acquisition risk. Furthermore, we address the advantages and limitations of historical treatments and emerging technologies under investigation to modify the vaginal microbiome, including: antibiotics, bacteriophages, probiotics, topicals, and engineered bacteria. By addressing the current state of vaginal microbiome knowledge and strategies for manipulation, we hope to amplify the growing calls for increased resources and research into vaginal microbial health, which will be essential to accelerating preventative efforts amongst the world's most vulnerable populations. [ABSTRACT FROM AUTHOR]

The article summarizes research conducted by Jonathan M. Carlson and others into the heterosexual transmission of the HIV-1 virus. Their work tested the hypothesis that the transmitting virus from the donor is selected based upon certain genetic characteristics. Results indicated that selection biases exist.