Translational Models to Predict Target Concentrations for Pre-Exposure Prophylaxis in Women

Abstract

The HIV epidemic remains a significant public health burden. Women represent half of the global HIV epidemic, yet there is an urgent need for a variety of prevention options to meet the needs of more women. Pre-exposure prophylaxis (PrEP) is a valuable prevention tool that uses antiretrovirals before a potential HIV exposure to prevent virus transmission. Development of effective preventive drug regimens for women is dependent on convenient dosing schedules and routes of administration, and on identifying defined target concentrations in mucosal tissues that provide complete protection against HIV transmission. There is a critical need for a translational model that can accurately predict in vivo target concentrations that are completely protective against HIV infection. There is no gold-standard preclinical model to predict PrEP efficacy. In this study, we review the strengths and limitations of three different preclinical models and their utility in predicting target concentrations in the female genital tract: humanized mice, non-human primates, and the ex vivo tissue model.

Keywords: HIV; PrEP; animal models; explants; female genital tract; pharmacology.

FIG. 1.

Scheme depicting the experimental design ex vivo (A). Explant Challenge and (B). Dose challenge. (A) In explant challenge, discarded tissue is collected from HIV-negative women and used to produce explants. Explants are then incubated with the drug of interest before being challenged with HIV. (B) Genital tissue biopsies are collected from HIV-negative women who previously took the drug of interest. The biopsies can be placed in culture directly or further processed into explants that are placed in culture and then are challenged with HIV. HIV, human immunodeficiency virus.