Elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.

Elevated inflammatory cytokines (EMCs) at mucosal surfaces have been associated with HIV susceptibility, but the underlying mechanisms remain unclear. We characterized the soluble mucosal proteome associated with elevated cytokine expression in the female reproductive tract. A scoring system was devised based on the elevation (upper quartile) of at least three of seven inflammatory cytokines in cervicovaginal lavage. Using this score, HIV-uninfected Kenyan women were classified as either having EMC (n=28) or not (n=68). Of 455 proteins quantified in proteomic analyses, 53 were associated with EMC (5% false discovery rate threshold). EMCs were associated with proteases, cell motility, and actin cytoskeletal pathways, whereas protease inhibitor, epidermal cell differentiation, and cornified envelope pathways were decreased. Multivariate analysis identified an optimal signature of 16 proteins that distinguished the EMC group with 88% accuracy. Three proteins in this signature were neutrophil-associated proteases that correlated with many cytokines, especially GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-1β (interleukin-1β), MIP-3α (macrophage inflammatory protein-3α), IL-17, and IL-8. Gene set enrichment analyses implicated activated immune cells; we verified experimentally that EMC women had an increased frequency of endocervical CD4(+) T cells. These data reveal strong linkages between mucosal cytokines, barrier function, proteases, and immune cell movement, and propose these as potential mechanisms that increase risk of HIV acquisition.

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin αβ 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 αβ blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of αβ 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 αβ binding. In addition, pre-HIV αβ 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 αβ 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 αβ 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 αβ expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-αβ monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting αβ integrin as a clinical intervention during HIV infection.

Several clinical trials have demonstrated that antiretroviral (ARV) drugs, taken as pre-exposure prophylaxis (PrEP), can prevent HIV infection1, with the magnitude of protection ranging from -49 to 86%2–11. While these divergent outcomes are thought to be due primarily to product adherence12, biological factors likely contribute13. Despite selective recruitment of higher risk participants for prevention trials, HIV risk is heterogeneous, even within higher risk groups14–16. To determine whether this heterogeneity could influence PrEP outcomes, we undertook a post-hoc prospective analysis of the CAPRISA 004 tenofovir 1% gel trial (n=774), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine pro-inflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% CI: 7 to 80%), compared to 3% (95% CI: −104 to 54%) if genital inflammation was present. Among high gel adherers, tenofovir protection was 75% (95% CI: 25 to 92%) in women without inflammation compared to −10% (95% CI: −184 to 57%) in women with inflammation. Host immune predictors of HIV risk may modify the effectiveness of HIV prevention tools; reducing genital inflammation in women may augment HIV prevention efforts.