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Preventing new HIV infections remains a global challenge. Young women continue to bear a disproportionate burden of infection. Oral pre-exposure prophylaxis (PrEP), offers a novel women-initiated prevention technology and PrEP trials completed to date underscore the importance of their inclusion early in trials evaluating new HIV PrEP technologies. Data from completed topical and systemic PrEP trials highlight the role of gender specific physiological and social factors that impact PrEP uptake, adherence and efficacy. Here we review the past and current developments of HIV-1 prevention options for women with special focus on PrEP considering the diverse factors that can impact PrEP efficacy. Furthermore, we highlight the importance of inclusion of female scientists, clinicians, and community advocates in scientific efforts to further improve HIV prevention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Karim, Archary, Barré-Sinoussi, Broliden, Cabrera, Chiodi, Fidler, Gengiah, Herrera, Kharsany, Liebenberg, Mahomed, Menu, Moog, Scarlatti, Seddiki, Sivro and Cavarelli.)

In order to establish productive infection in women, HIV must transverse the vaginal epithelium and gain access to local target cells. Genital inflammation contributes to the availability of HIV susceptible cells at the female genital mucosa and is associated with higher HIV transmission rates in women. Factors that contribute to genital inflammation may subsequently increase the risk of HIV infection in women. Semen is a highly immunomodulatory fluid containing several bioactive molecules with the potential to influence inflammation and immune activation at the female genital tract. In addition to its role as a vector for HIV transmission, semen induces profound mucosal changes to prime the female reproductive tract for conception. Still, most studies of mucosal immunity are conducted in the absence of semen or without considering its immune impact on the female genital tract. This review discusses the various mechanisms by which semen exposure may influence female genital inflammation and highlights the importance of routine screening for semen biomarkers in vaginal specimens to account for its impact on genital inflammation., (© 2021 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Genital inflammation significantly increases the risk for HIV infection. The seminal environment is enriched in pro-inflammatory cytokines and chemokines. Here, we investigated the interplay between semen cytokines and humoral immunity to understand whether the characteristics of semen antibodies are associated with genital inflammation. In 36 HIV-infected and 40 HIV-uninfected mens' semen, HIV-specific antibodies (gp120, gp41, p66, and p24), immunoglobulin (Ig) subclasses, isotypes and cytokines, using multiplex assays, were measured. Semen IgG1, IgG3, and IgM were significantly higher in HIV-infected compared to HIV-uninfected men ( p < 0.05). In HIV-uninfected men, pro-inflammatory cytokines IL-6, IL-8, and MCP-1 significantly correlated with IgG1 and total IgG (IgG1+IgG2+IgG3+IgG4) (both r ≥0.55; p ≤0.001). Total IgG in HIV-infected men correlated to HIV-specific antibodies in the semen irrespective of antiretroviral (ARV) use. In HIV-infected, ARV-treated men, p66 and gp41-specific antibodies were inversely correlated with IL-6 and MIP-1α (both r ≥-0.65, p ≤0.03). In HIV-infected, ARV-naïve men, p24 and gp120-specific antibodies correlated significantly with pro-inflammatory TNF-α ( r ≥0.44, p ≤0.03), while p24 antibodies correlated significantly with chemokine MIP-1β ( r = 0.45; p = 0.02). Local cytokines/chemokines were associated with the mucosal-specific Ig subclasses which likely effect specific antibody functions. Together, these data inform on mucosal-specific immunity that may be elicited in the male genital tract (MGT) in future vaccines and/or combination HIV prevention strategies.

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α 4 β 7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α 4 β 7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α 4 β 7 + peripheral blood CD4 + T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α 4 β 7 binding. In addition, pre-HIV α 4 β 7 + CD4 + T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4 + T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α 4 β 7 + CD4 + T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4 + T cells expressing α 4 β 7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α 4 β 7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α 4 β 7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α 4 β 7 integrin as a clinical intervention during HIV infection., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Introduction: Optimizing methods for genital specimen collection to accurately characterize mucosal immune responses is a priority for the HIV prevention field. The menstrual cup (MC) has been proposed as an alternative to other methods including cervicovaginal lavage (CVL), but no study has yet formally compared these two methods., Methods: Forty HIV-infected, antiretroviral therapy-naïve women from the CAPRISA 002 acute HIV infection cohort study were randomized to have genital fluid collected using the MC with subsequent CVL, or by CVL alone. Qualitative data, which assessed levels of comfort and acceptability of MC using a 5-point Likert scale, was collected. Luminex multiplex assays were used to measure HIV-specific IgG against multiple gene products and 48 cytokines., Results: The majority (94%) of participants indicated that insertion, wearing and removal of the MC was comfortable. Nineteen MCs with 18 matching, subsequent CVLs and 20 randomized CVLs were available for analysis. Mucosal IgG responses against four HIV-antigens were detected in 99% of MCs compared to only 80% of randomized CVLs (p = 0.029). Higher specific antibody activity and total antibodies were observed in MCs compared to CVL (all p<0.001). In MCs, 42/48 (88%) cytokines were in the detectable range in all participants compared to 27/48 (54%) in CVL (p<0.001). Concentrations of 22/41 cytokines (53.7%) were significantly higher in fluid collected by MC. Both total IgG (r = 0.63; p = 0.005) and cytokine concentrations (r = 0.90; p<0.001) correlated strongly between MC and corresponding post-MC CVL., Conclusions: MC sampling improves the detection of mucosal cytokines and antibodies, particularly those present at low concentrations. MC may therefore represent an ideal tool to assess immunological parameters in genital secretions, without interfering with concurrent collection of conventional CVL samples.

Despite an influx of T cells to the cervix during HIV infection, genital T cells are not associated with control of HIV shedding. CD57 expression by T cells has been associated with enhanced migratory potential and CD57+ T cells have been shown to accumulate in tissues during the late stages of HIV disease. We investigated the impact of HIV-infection and clinical status on the expression of CD57 by T cells from the female genital tract in 13 HIV-infected and 5 uninfected women. We found that cervical and blood-derived T cells expressed similar frequencies of CD57. The frequency of CD57 expression by cervical or blood T cells was not associated with clinical status (CD4 counts). No impairment in IFN-gamma production by CD57+ T cells from the genital tract was observed. We conclude that increased T cell senescence does not appear to be a hallmark of genital mucosal HIV-1 infection., (Copyright 2009 Elsevier Inc. All rights reserved.)