Cervical inflammation and immunity associated with hormonal contraception, pregnancy, and HIV-1 seroconversion

Abstract

Objective: Hormonal contraception (HC), younger age, and pregnancy have been associated with increased HIV risk in some studies. We sought to elucidate the biological mechanisms for these associations.

Design: Case-control selection of specimens from a large, prospective, clinical study.

Methods: We enrolled and followed 4531 HIV-negative women from Uganda and Zimbabwe using either the injectable depo-medroxyprogesterone acetate (DMPA), combined oral contraception, or no HC (NH). Innate immunity mediators were measured in cervical samples collected from women at their visit before HIV seroconversion (n = 199) and matched visits from women remaining HIV uninfected (n = 633). Generalized linear models were applied after Box-Cox power transformation.

Results: Higher RANTES and lower secretory leukocyte protease inhibitor (SLPI) levels were associated with HIV seroconversion. DMPA users had higher RANTES and lower BD-2 levels. Most inflammation-promoting and/or inflammation-inducible mediators were higher [interleukin (IL)-1β, IL-6, IL-8, MIP-3α, vascular endothelial growth factor, and SLPI], and the protective BD-2 and IL-1RA:IL-1β ratio were lower among combined oral contraception users. Pregnant women showed a similar cervical immunity status (higher IL-1β, IL-6, IL-8, vascular endothelial growth factor, SLPI, and IL-1RA; lower IL-1RA:IL-1β). Age <25 years was associated with lower SLPI, IL-8, MIP-3α but higher IL-1RA:IL-1β. Zimbabwean women (with higher HIV seroconversion rates) had overall higher pro-inflammatory and lower anti-inflammatory protein levels than Ugandan women.

Conclusions: HC use, pregnancy, and young age alter cervical immunity in different ways known to increase risk of HIV, for example, through increased levels of pro-inflammatory cytokines or decreased levels of SLPI. Higher levels of RANTES may be one factor underlying a possible association between DMPA use and risk of HIV acquisition.