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.
*Clinical Sciences, FHI 360, Durham, NC;
†Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
‡CONRAD, Eastern Virginia Medical School, Arlington, VA;
§Biostatistics, FHI 360, Durham, NC;
‖Department of Obstetrics and Gynaecology, University of Zimbabwe, Harare, Zimbabwe;
¶Department of Medicine, Case Western Reserve University, Cleveland, OH; and
#Department of Obstetrics and Gynecology, CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA.
Correspondence to: Charles Morrison, PhD, Clinical Sciences, FHI 360, 359 Blackwell Street, Suite 200, Durham, NC 27701, (e-mail: firstname.lastname@example.org), or Raina N. Fichorova, MD, PhD, Brigham and Women's Hospital, 221 Longwood Avenue, RF468, Boston, MA 02115, USA, (e-mail: email@example.com).
Supported by U.S. federal funds from the Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health through an Interagency Agreement with the United States Agency for International Development (USAID) (GHO-A-00-09-00016-00); and from funds from USAID provided to CONRAD (GPO-A-00-08-00005-00). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The content of this publication does not necessarily reflect their views or policies nor does mention of trade names, commercial products, or organizations imply endorsement by FHI 360, Women's Hospital, CONRAD, Case Western Reserve University or the US Government.
Ethics statement: The study protocol received a nonhuman subject determination (use of de-identified data) from the Office of International Research Ethics at FHI 360 and the Institutional Review Board at Brigham and Women's Hospital.
The authors have no conflict of interest to disclose.
C.M. and R.F. have contributed equally. Designed the study: C.S.M., R.F., C.M., P.C., and G.D. Analyzed the HC-HIV data: P.C., C.K., C.S.M., R.F., C.M., and G.D; Conducted the measurements of biomarkers: R.F. Wrote the first draft of the article: C.S.M., R.F., and P.C. Contributed to the writing of the article: C.M., G.D., C.K., T.C., and R.S. Agree with the article's results and conclusions: C.S.M., R.F., C.M., P.C., C.K., T.C., R.S., and G.D.
Received December 30, 2013
Accepted December 30, 2013