Comparative Evaluation of Virus Transmission Inhibition by Dual-Acting Pyrimidinedione Microbicides Using the Microbicide Transmission and Sterilization Assay

Abstract

ABSTRACT In the absence of a fully effective human immunodeficiency virus (HIV) vaccine, topical microbicides represent an important strategy for preventing the transmission of HIV through sexual intercourse, the predominant mode of HIV transmission worldwide. Although a comprehensive understanding of HIV transmission has not yet emerged in the microbicide field, it is likely the result of rapid infection of monocyte-derived cells in the vaginal mucosa by CCR5-tropic viruses. Inhibition of HIV transmission requires agents that prevent entry, fusion, reverse transcription, or other preintegrative replication events or agents which directly inactivate HIV or modulate the target cells to render them uninfectible. In vitro assays typically used to evaluate the ability of a microbicide to prevent virus transmission use epithelial or human osteosarcoma-derived cells or immune cells more relevant to the development of anti-HIV therapeutic agents and quantify virus production at short time intervals following infection. We have developed a microbicide transmission and sterilization assay (MTSA) to more sensitively and quantitatively evaluate virus transmission in cell culture in the presence of microbicidal compounds. Results obtained with the MTSA demonstrate that the inhibitory capacity of microbicides is often overestimated in short-term transmission inhibition assays, while some compounds yield equivalent inhibitory results, indicating a biological relevance for the MTSA-based evaluations to identify superior potent microbicides. The MTSA defines the concentration of the microbicide required to totally suppress the transmission of virus in cell culture and may thus help define the effective concentration of the microbicide required in a formulated microbicide product.