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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. [ABSTRACT FROM AUTHOR]

Genital inflammation (GI) undermines topical human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) efficacy through unknown mechanisms. Here, associations between activated endocervical CD4 + T-cell numbers and higher deoxyadenosine triphosphate (dATP) concentrations suggest that competition for intracellular metabolites within HIV target cells may reduce the efficacy of antiretroviral-based PrEP in women with GI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Semen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen‐induced alterations are likely short‐lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations. Methods: We assessed stored genital specimens from 152 HIV‐negative KwaZulu‐Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two‐year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate‐specific antigen (PSA) by ELISA, whereas Y‐chromosome DNA (YcDNA) detection and quantification were conducted by RT‐PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA−YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T‐cell frequencies were assessed in cytobrushes by flow‐cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits. Results: Here, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA−YcDNA+ and 67% (433/651) were PSA−YcDNA−. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV‐2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier‐related proteins (MMP‐2, TIMP‐1 and TIMP‐4) and activated CD4+CCR5+HLA‐DR+ T cells (β = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA‐DR+ T cells (β = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro‐inflammatory cytokines (including IL‐6, TNF‐α, IP‐10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021). Conclusions: More recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV‐associated microbes, which declined by three to fifteen days of post‐exposure. Although transient, semen‐induced alterations may have implications for HIV susceptibility in women. [ABSTRACT FROM AUTHOR]

Genital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) system to understand the contribution of TLR stimulation in inducing inflammation and the activation of target T cells, and its effect on HIV susceptibility. PBMCs were stimulated with TLR agonists LPS (TLR4), R848 (TLR7/8), and Pam3CSK4 (TLR1/2), and then infected with HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines in cell culture supernatants. Flow cytometry was used to measure the activation state (CD38 and HLA-DR), and CCR5 expression on CD4+ and CD8+ T cells. Although TLR agonists induced higher cytokine and chemokine secretion, they did not significantly activate CD4+ and CD8+ T cells and showed decreased CCR5 expression relative to the unstimulated control. Despite several classes of inflammatory cytokines and chemokines being upregulated by TLR agonists, CD4+ T cells were significantly less infectable by HIV after TLR4-stimulation than the unstimulated control. These data demonstrate that the inflammatory effects that occur in the presence TLR agonist stimulations do not necessarily translate to the activation of T cells. Most importantly, the finding that TLR4-stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection in this in vitro system strongly suggests that the increased chemokine and possible antiviral factor expression induced by these TLR agonists play a powerful although complex role in determining HIV infection risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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-γ 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 &y& Elsevier]

Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2–5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence. Cervicovaginal inflammation and human papillomavirus (HPV) are separately associated with increased risk of HIV acquisition. Here the authors longitudinally profile 48 cervicovaginal cytokines and HPV status in a large observational HIV high-risk cohort, and show the same cytokines associate with HPV infection and HIV risk. [ABSTRACT FROM AUTHOR]

Initiation of highly active antiretroviral therapy (HAART) for HIV-infected individuals is associated with control of viremia, improved CD4 counts, and declining systemic HIV-specific immune responses. While HAART effectively reduces plasma viremia, it remains unclear how effectively antiretroviral drugs reach mucosal surfaces, such as those of the genital tract. The aim of this study was to determine the effect of HAART on genital tract CD4 T cell reconstitution, HIV shedding, and HIV-specific T cell responses. Cervical cytobrush and blood specimens were obtained from 35 HIV-infected, HAART-naïve women and 27 women on HAART in order to investigate HIV Gag-specific T cell responses by intracellular gamma interferon (IFN-γ) staining. Interleukin 1β (IL-1β), IL-6, and IL-8 concentrations were measured by enzyme-linked immunosorbent assays (ELISA). We show that for HIV-infected women, HAART is associated with significantly improved CD4 T cell counts both in blood and at the cervix. While HAART effectively suppressed both blood and cervical viremia, HIV-specific CD8 T cell responses in blood were lost, while those at the cervix were preserved. [ABSTRACT FROM AUTHOR]