Dataset Information

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel.

ABSTRACT: The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and systemic antibody responses. Linear mixed effect modeling and partial least squares discriminant analysis was used to identify multivariate antibody signatures associated with tenofovir use. There were significantly higher response rates to gp120 Env (P=0.03), p24 (P=0.002), and p66 (P=0.009) in plasma and GT in women assigned to tenofovir than placebo gel at multiple time points post infection. Notably, p66 IgA titers in the GT and plasma were significantly higher in the tenofovir compared with the placebo arm (P<0.05). Plasma titers for 9 of the 10 HIV-IgG specificities predicted GT levels. Taken together, these data suggest that humoral immune responses are increased in blood and GT of individuals who acquire HIV infection in the presence of tenofovir gel.

SUBMITTER: Archary D

PROVIDER: S-EPMC4848129 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel.

Archary D D Seaton K E KE Passmore J S JS Werner L L Deal A A Dunphy L J LJ Arnold K B KB Yates N L NL Lauffenburger D A DA Bergin P P Liebenberg L J LJ Samsunder N N Mureithi M W MW Altfeld M M Garrett N N Karim Q Abdool QA Karim Ss Abdool SA Morris L L Tomaras G D GD

Mucosal immunology 20160127 3

The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and syst ...[more]

PMID: 26813340

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Project description:Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.ClinicalTrials.gov NCT00594373.

Dataset Information

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel.

Publications

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel.

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