Oral Pre-Exposure Prophylaxis by Anti-Retrovirals Raltegravir and Maraviroc Protects against HIV-1 Vaginal Transmission in a Humanized Mouse Model

Abstract

Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.

HIV sexual transmission and microbicides

“…Others have explored and shown the protective effect of the integrase inhibitor Raltegravir against vaginal transmission upon oral PrEP in a humanised mouse model [265].…”

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

“…Two new generation humanized models that encompass hu-HSC and BLT mouse models are currently used. Indeed, several ARTs have been successfully tested in these hu-mouse models to determine their in vivo efficacy against HIV-1 transmission (10–16). These ARTs include tenofovir, emtricitabine, maraviroc and raltegravir (RAL) that act via different mechanisms on various viral and cellular targets.…”

Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues

“…Proof of concept that MVC could prevent HIV transmission was first provided in humanized RAG-hu mice that received oral (62 mg/kg) or topical (5 mM) MVC gel and were exposed vaginally to HIV (9,10). Studies in macaques also showed efficacy of vaginal gels containing MVC at concentrations exceeding 1 mM.…”