P18.04
Background: HIV continues to be a serious threat to the global public health, especially among women in developing countries. Microbicides may offer an alternative approach for blocking transmission of HIV when condom use cannot be negotiated with male partners. We have developed a novel HIV microbicide candidate. Avaren-Fc (AvFc), consisting of oligomannose-specific lectin Avaren dimerized by fusion to the Fc region of human IgG, has shown low-nanomolar antiviral activity against multiple HIV type 1 and type 2 clinical isolates. Moreover, AvFc induced antibody-dependent cell-mediated cytotoxicity. Cognizant of the imperative that microbicides not induce epithelial damage or inflammatory responses, here we show that AvFc is nonirritating and noninflammatory in human peripheral blood mononuclear cells (hPBMCs), in human vaginal epithelial tissue (hVET), and in vivo in the rabbit vaginal irritation (RVI) model.
Methods: Human PBMCs were treated with AvFc up to 100μg/ml, nonoxynol-9 (N9), or Concanavalin A (ConA) and accessed for viability, induction of activated cells, and induction of proinflammatory cytokines and chemokines. Reconstituted hVET grown on membrane filters were exposed to AvFc up to 0.1% (w/v), formulation buffer, or 0.2% N9 for 72 hours. Using the RVI model, rabbits were exposed daily to AvFc up to 0.1% (w/v), vehicle control, or 2% Benzalkonium chloride (BZK) for 10 days. In both models, tissue damage was evaluated by histological assessment. Furthermore, viability was evaluated by MTT analysis, and barrier disruption was accessed by transepithelial electrical resistance in the hVET.
Results: Unlike ConA or N9, AvFc did not show any cytotoxicity, proinflammatory cytokine release or mitogenicity in hPBMCs at maximal antiviral concentrations. In addition AvFc did not induce any discernible toxic or inflammatory effects in both vaginal models compared to N9 or BZK.
Conclusions: Taken together, these results highlight AvFc's candidacy as a safe microbicide with broad and potent anti-HIV potential.
