P25.05
Background: Topically applied microbicides potently inhibit HIV in vitro but largely failed to exert protective effects in clinical trials. We explored whether the ability of semen to enhance HIV infection affects the antiviral efficacy of various classes of microbicides and antiretrovirals (ARVs).
Methods: HIV infection assays were performed in the presence or absence of semen (or SEVI amyloid fibrils) in cell lines and primary PBMCs; IC50 values of ARVs were determined and evaluated.
Results: We demonstrate that the ability of semen to enhance HIV infection in vitro markedly impairs the antiviral efficacy of ARVs that target virion components by 10 to 20-fold. These ARVs include polyanions, neutralizing antibodies, NRTI and NNRTI's, and inhibitors against HIV-1 Integrase and Protease. Similar results were obtained using synthetic SEVI fibrils. In contrast, semen deficient of amyloids and lacking the ability to enhance HIV infection did not impair the antiviral activity of ARVs. In direct contrast, the CCR5 antagonist Maraviroc (MVC) blocked mock and semen-exposed virus with similar efficacy. Notably, the concentrations of MVC required to block semen-exposed virus infection of PBMCs are lower than those that can be achieved in the genital tract after oral administration of the drug.
Conclusions: Our data show that the HIV enhancing activity of amyloids in semen undermines the antiviral efficacy of ARVs that target viral components, which might explain why such microbicides largely failed in clinical trials. In contrast, MVC, which targets a host protein that is present at constant amounts at the cell surface, retained activity in the presence of semen. These results suggest that compounds targeting cellular components may be advantageous for microbicide development. Since semen is the main vector for the spread of the AIDS pandemic, we recommend testing future candidate microbicides against semen-exposed virus to identify those agents that retain potent antiviral activity during sexual virus transmission.
