The molecular basis of nonoxynol-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus type 1 transmission.
Topical microbicides are being sought to prevent sexually transmitted diseases by inactivating pathogens while preserving or enhancing the natural mucosal barrier. Serious public health concerns were raised by a recent phase 3 clinical trial that showed that nonoxynol-9 (N-9), a leading microbicide candidate widely used as an over-the-counter spermicide, may actually increase human immunodeficiency virus type 1 (HIV-1) transmission. The present study links N-9-induced vaginal inflammation to increased risk of HIV-1 infection. Analysis of molecular and cellular components in cervicovaginal secretions, as well as results from in vitro activation of cervicovaginal epithelial cells and U1/HIV promonocytic cells, showed that multiple N-9 use can promote HIV-1 transmission through interleukin-1-mediated NF-kappaB activation, which leads to chemokine-induced recruitment of HIV-1 host cells and increased HIV-1 replication in infected cells. Furthermore, this study identifies in vitro and in vivo model systems for monitoring undesirable proinflammatory effects of microbicides and other vaginal products.
Fichorova
R N
RN
Fearing Research Laboratory, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Thorn-217, Boston, MA 02115, USA. rfichorova@rics.bwh.harvard.edu
Tucker
L D
LD
Anderson
D J
DJ
D000328:Adult; D002461:Cell Line, Transformed; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015658:HIV Infections / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017137:Nonoxynol / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D007507:Therapeutic Irrigation; D014407:Tumor Cells, Cultured; D014621:Vagina / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014627:Vaginitis / Q000139:chemically induced*
D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D016328:NF-kappa B; D017137:Nonoxynol