Abstract
In the past few years, the transdisciplinary field of HIV prevention has reached several milestones. Topically applied tenofovir gel provided significant protection from sexual transmission of HIV in a large-scale clinical trial and oral Truvada (emtricitabine/tenofovir disoproxil fumarate) was recently approved for preexposure prophylaxis (PrEP) following two successful clinical trials in men and women. These achievements are tempered by the disappointing results of other clinical trials, which highlight the complexities of prevention research. In this perspective, we discuss scientific and developmental gaps for topical chemoprophylaxis of the sexual transmission of HIV, which depends on the complex interactions between the pharmacokinetics and pharmacodynamics of drugs, formulation and delivery systems, anatomic site of transmission, and host mucosal immune defenses. Despite the considerable time and resources devoted to unraveling the initial steps in sexual transmission of HIV, current knowledge is based on animal models and human explanted tissue, which may not fully recapitulate what happens clinically. Understanding these events, including the role that sex hormones, semen, and mucosal secretions play in transmission, and the interplay between innate immunity, the mucosal environment, and drug efficacy is paramount. This drives some of the most pressing questions in the field.