Biocompatibility of solid-dosage forms of anti-human immunodeficiency virus type 1 microbicides with the human cervicovaginal mucosa modeled ex vivo.
Topical anti-human immunodeficiency virus (HIV) microbicides are being sought to reduce the spread of HIV type 1 (HIV-1) during sexual intercourse. The success of this strategy depends upon the selection of formulations compatible with the natural vaginal mucosal barrier. This study applied ex vivo-modeled human cervicovaginal epithelium to evaluate experimental solid-dosage forms of the anti-HIV-1 microbicide cellulose acetate 1,2-benzenedicarboxylate (CAP) and over-the-counter (OTC) vaginal products for their impact on inflammatory mediators regarded as potential HIV-1-enhancing risk factors. We assessed product-induced imbalances between interleukin-1alpha (IL-1alpha) and IL-1beta and the natural IL-1 receptor antagonist (IL-1RA) and changes in levels of IL-6, tumor necrosis factor alpha, IL-8, gamma interferon inducible protein 10 (IP-10), and macrophage inflammatory protein 3alpha (MIP-3alpha), known to recruit and activate monocytes, dendritic cells, and T cells to the inflamed mucosa. CAP film and gel formulation, similarly to the hydroxyethylcellulose universal vaginal placebo gel and the OTC K-Y moisturizing gel, were nontoxic and caused no significant changes in any inflammatory biomarker. In contrast, OTC vaginal cleansing and contraceptive films containing octoxynol-9 or nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles. IL-1alpha, IL-1beta, IL-8, and IP-10 were increased after treatment with both OTC vaginal cleansing and contraceptive films; however, MIP-3alpha was significantly elevated by the N-9-based film only (P < 0.01). Although both films increased extracellular IL-1RA, the cleansing film only significantly elevated the IL-1RA/IL-1 ratio (P < 0.001). The N-9-based film decreased intracellular IL-1RA (P < 0.05), which has anti-inflammatory intracrine functions. This study identifies immunoinflammatory biomarkers that can discriminate between formulations better than toxicity assays and should be clinically validated in relevance to the risk of HIV-1 acquisition.
Trifonova
Radiana T
RT
Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.
Pasicznyk
Jenna-Malia
JM
Fichorova
Raina N
RN
D000282:Administration, Intravaginal; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000494:pharmacology*; D001672:Biocompatible Materials / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014621:Vagina / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D000890:Anti-Infective Agents; D001672:Biocompatible Materials; D016207:Cytokines; D014622:Vaginal Creams, Foams, and Jellies