title: 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.
  
  
  METHODS
  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.
authors.affiliation: *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.
authors.forename: Charles
authors.initials: C
authors.lastname: Morrison
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.forename: Chris
authors.initials: C
authors.lastname: Mauck
authors.forename: Pai-Lien
authors.initials: PL
authors.lastname: Chen
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kwok
authors.forename: Tsungai
authors.initials: T
authors.lastname: Chipato
authors.forename: Robert
authors.initials: R
authors.lastname: Salata
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002584:Cervix Uteri / Q000187:drug effects* / Q000276:immunology; D054418:Chemokine CCL20 / Q000097:blood; D018946:Chemokine CCL5 / Q000097:blood; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000009:adverse effects*; D016207:Cytokines / Q000097:blood; D005260:Female; D006679:HIV Seropositivity / Q000453:epidemiology* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced*; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000009:adverse effects; D011247:Pregnancy; D011446:Prospective Studies; D012307:Risk Factors; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000097:blood; D014454:Uganda / Q000453:epidemiology; D055815:Young Adult; D015030:Zimbabwe / Q000453:epidemiology
chemical_list: C108355:CCL20 protein, human; C483024:CCL5 protein, human; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D003271:Contraceptive Agents, Female; D016207:Cytokines; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D017258:Medroxyprogesterone Acetate