Immune parameters of HIV susceptibility in the female genital tract before and after penile-vaginal sex

Abstract

Background In women, most HIV infections are acquired through penile-vaginal sex. Inflammation in the female genital tract (FGT) increases the risk of HIV acquisition and transmission, likely through recruitment of HIV target cells and disruption of epithelial barrier integrity. Although sex may have important immune and epithelial effects, the impact of receptive penile-vaginal sex on the immune correlates of HIV susceptibility in the female genital tract is not well described. Methods STI-free heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the serial collection of cervical secretions (CVS), endocervical cytobrushes, blood and semen before and up to 72 h after either condomless (n = 29) or condom-protected (n = 8) penile-vaginal sex. Immune cells were characterized by flow cytometry, and immune factors including cytokines and soluble E-cadherin (sE-cad; a marker of epithelial disruption) were quantified by multiplex immunoassay. Co-primary endpoints were defined as levels of IP-10 and IL-1α, cytokines previously associated with increased HIV susceptibility. Results Here we show that cervicovaginal levels of vaginal IP-10, sE-cad and several other cytokines increase rapidly after sex, regardless of condom use. The proportion of endocervical HIV target cells, including Th17 cells, activated T cells, and activated or mature dendritic cells (DCs) also increase, particularly after condomless sex. Although most of these immune changes resolve within 72 h, increases in activated cervical CD4 + T cells and Tcm persist beyond this time. Conclusions Penile-vaginal sex induces multiple genital immune changes that may enhance HIV susceptibility during the 72 h post-sex window that is critical for virus acquisition. This has important implications for the mucosal immunopathogenesis of HIV transmission.

Soluble E‐cadherin: A marker of genital epithelial disruption

“…In the current study, we demonstrate that a pure mechanical disruption in the absence of proin ammatory stimuli caused an immediate increase in sE-cad levels, and we con rmed the association between sE-cad levels in genital secretions and genital epithelial disruption in both the male and female genital tract. Interestingly, the degree of sEcad elevation in supernatant following physical disruption in vitro was similar to the increases observed in cervicovaginal secretions immediately following vaginal intercourse, regardless of condom use [24], strongly suggesting that the latter is caused by epithelial disruption as a result of penile-vaginal sex.…”

“…In the current study, we demonstrate that a pure mechanical disruption in the absence of additional proinflammatory stimuli caused an immediate increase in sE‐cad levels, and we confirmed the association between sE‐cad levels in genital secretions and genital epithelial disruption in both the male and female genital tract. Interestingly, there was a similar increase in sE‐cad observed in cervicovaginal secretions immediately following vaginal intercourse, regardless of condom use, 29 strongly suggesting that sE‐cad elevation is caused by epithelial disruption as a result of penile‐vaginal sex. However, elevated sE‐cad may not only indicate immediate physical disruption but may also indicate epithelial growth and remodeling, as indicated by the progressive increase in sE‐cad levels over time in our undisrupted control wells.…”

“…In the current study, we demonstrate that a pure mechanical disruption in the absence of additional proinflammatory stimuli caused an immediate increase in sE-cad levels, and we confirmed the association between sE-cad levels in genital secretions and genital epithelial disruption in both the male and female genital tract. Interestingly, there was a similar increase in sE-cad observed in cervicovaginal secretions immediately following vaginal intercourse, regardless of condom use, 29 strongly suggesting that sE-cad elevation is caused by epithelial dis- In contrast, IL-6 levels in the endocervical monolayer supernatant continued to increase for at least 24 h following physical disruption, suggesting that elevations in this cytokine are due to transcriptiondependent processes rather than cytosolic release. The fact that foreskin monolayer disruption did not induce release of IL-1α or IL-1β…”

The initial interplay between HIV and mucosal innate immunity

“…Under physiological conditions, the FGT environment contains less cytokines and immune cells. During inflammation, there is the recruitment of immune cells at the infection site, which are the target of the infection, and the production of cytokines, such as TNF and IL-1a, responsible for the disruption of epithelial barrier integrity ( 131 , 136 , 137 ). Multiple factors are involved in genital inflammations, such as hygiene, sexually transmitted diseases, and hormonal contraceptives ( 138 , 139 ).…”

Optimizing the vaginal microbiome as a potential strategy to reduce heterosexual HIV transmission

“…Such factors include sexual activity, menstrual cycle stage, and contraceptive use. In particular, male-to-female HIV transmission often occurs during penile-vaginal sex, and penile-vaginal sex itself-particularly with a new male partner-is associated with the disruption of the female genital microbiota and genital inflammation [45,65,66]. Therefore, sexual activity and new sexual partners may be key confounders in the relationship between BV and HIV acquisition.…”