HIV-1-Neutralizing IgA Detected in Genital Secretions of Highly HIV-1-Exposed Seronegative Women on Oral Preexposure Prophylaxis

Abstract

Although nonhuman primate studies have shown that simian immunodeficiency virus/simian-human immunodeficiency virus (SIV/SHIV) exposure during preexposure prophylaxis (PrEP) with oral tenofovir can induce SIV immunity without productive infection, this has not been documented in humans. We evaluated cervicovaginal IgA in Partners PrEP Study participants using a subtype C primary isolate and found that women on PrEP had IgA with higher average human immunodeficiency virus type 1 (HIV-1)-neutralizing magnitude than women on placebo (33% versus 7%; P ‫؍‬ 0.008). Using a cutoff of >90% HIV-1 neutralization, 19% of women on-PrEP had HIV-1-neutralizing IgA compared to 0% of women on placebo (P ‫؍‬ 0.09). We also estimated HIV-1 exposure and found that the proportion of women with HIV-1-neutralizing IgA was associated with the level of HIV-1 exposure (P ‫؍‬ 0.04). Taken together, our data suggest that PrEP and high levels of exposure to HIV may each enhance mucosal HIV-1-specific humoral immune responses in sexually exposed but HIV-1-uninfected individuals. IMPORTANCE Although there is not yet an effective HIV-1 vaccine, PrEP for at-risk HIV-1-uninfected individuals is a highly efficacious intervention to prevent HIV-1 acquisition and is currently being recommended by the CDC and WHO for all individuals at high risk of HIV-1 acquisition.We previously demonstrated that PrEP use does not enhance peripheral blood HIV-1-specific T-cell responses in HIV-exposed individuals. Here, we evaluate for cervicovaginal HIV-neutralizing IgA responses in genital mucosal secretions of HIV-exposed women, which is likely a more relevant site than peripheral blood for observation of potentially protective immune events occurring in response to sexual HIV-1 exposure for various periods. Furthermore, we assess for host response in the context of longitudinal quantification of HIV-1 exposure. We report that HIV-neutralizing IgA is significantly correlated with higher HIV-1 exposure and, furthermore, that there are more women with HIV-1-neutralizing IgA in the on-PrEP group than in the placebo group. T he development of novel human immunodeficiency virus type 1 (HIV-1) prevention strategies that reduce HIV-1 susceptibility and impart long-term immune protection is a high priority. Four randomized, placebo-controlled clinical trials, conducted among diverse geographic and at-risk populations, have demonstrated that HIV-1-uninfected persons taking a daily oral antiretroviral as preexposure prophylaxis (PrEP)-either tenofovir (TDF) alone or coformulated with emtricitabine (TDF/FTC)-are at substantially reduced risk of HIV-1 acquisition (1-4). In recognition of this, WHO has recently recommended PrEP use for all individuals at substantial risk of HIV-1. Since PrEP will increasingly be used as part of standard care in the context of HIV-1 vaccine studies, it is essential to better understand the potential effects of PrEP on the host immune response to HIV-1.While the primary mechanism of protection afforded by PrEP is thought to be through...

Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection

“…We measured the effect of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), or oral TDF alone, on the gastrointestinal tract, the female reproductive tract, and blood from three clinical trials of oral PrEP in HIV-uninfected individuals: the Microbicide Trials Network trial 017 9 (MTN-017); ACTU-3500 (first reported here, see Methods); and the Genital Mucosal Substudy (GMS) 10 of the Partners PrEP Study 8 . We analyzed gene expression by microarray, RNA sequencing (RNAseq) and digital droplet PCR (ddPCR); and protein expression by mass spectrometry and microscopy.…”

“…Samples were used from four studies, which are described in Table 1. Two sets of samples were used from the Genital Mucosal Substudy (GMS) 10 Table 1). ACTU-3500 was reviewed through the University of Washington Institutional Review Board, number 49167.…”

The Multifaceted Nature of Immunoglobulin A and Its Complex Role in HIV

“…Levels of cervical mucosal IgA have been correlated with the frequency of repeated exposure in the absence of any correlation with resistance. 97 Furthermore, the recurrent presence of neutralizing anti-HIV IgA in these cohort studies 87,88,97,98 could possibly be linked to prevention of persistent systemic HIV infection. The reduced risk of infection in these individuals is, however, most likely dependent on multiple interactive factors, and understanding the mechanisms of protection among these populations will likely be key to designing effective vaccine strategies.…”

“…A protective role for mucosal IgA is often inferred from studies of individuals referred to as highly exposed to HIV, but IgG seronegative (HESN) individuals, despite repeated sexual exposure to seropositive partners. Many of these studies report detection of anti-HIV IgAs in serum, 86 genitourinary fluids, [86][87][88] and saliva 89 of these individuals who are often from studies examining sex worker cohorts. Some of these studies have correlated resistance with HIV with high levels of IgA against the envelope protein in vaginal secretions and saliva of these HESN individuals.…”

Mucosal Antibodies: Defending Epithelial Barriers against HIV-1 Invasion

“…For women whose cervical/vaginal secretions had neutralizing IgA, the OR for HIV-1 acquisition was 0.31. A later study involving women enrolled in a Pre-Exposure Prophylaxis (PrEP study) also found anti-HIV-1 neutralizing IgA in the cervical/vaginal secretions [56]: the patient population also involved HEPS individuals. Together, these intriguing data from African men and women give a strong indication that mucosal IgA responses, perhaps IgA1 responses, are linked to lowering the risk of HIV-1 acquisition through sexual exposures.…”