Candidate Microbicides and Their Mechanisms of Action

Abstract

The development of prevention strategies against sexual transmission of human immunodeficiency-1 virus (HIV-1) is essential to curb the rate of new infections. New prevention options include microbicides, many of which are based on antiretroviral (ARV) drugs targeting different stages of the viral replication cycle including: viral entry and fusion; reverse transcription; integration; and viral maturation through proteolytic clevage. In this review, we discuss current and new potential candidate microbicides designed to prevent mucosal HIV acquisition. Preclinical methods, including cellular, tissular, and animal models, used to assess candidate microbicides and evaluate their prioritization for progress through the product development pipeline are reviewed in context with a rapidly evolving clinical landscape.

Oligonucleotide-Lipid Conjugates Forming G-Quadruplex Structures Are Potent and Pangenotypic Hepatitis C Virus Entry Inhibitors In Vitro and Ex Vivo

“…Lipoquads inhibit HCV ex vivo in a mucosal model. To assess lipoquad activity ex vivo, we tested lipoquads in a mucosal model based on ex vivo viral challenge of colorectal tissue explants (38,39). This model allowed us to evaluate the potency of lipoquads as an HCV entry inhibitor against a reporter HCV, Jc1FLAG(p7-nsGluc2A), by measurement of Gaussia luciferase expressed and secreted upon viral entry, translation, and/or replication of the HCV genome (40).…”

Short Communication: Limited Anti-HIV-1 Activity of Maraviroc in Mucosal Tissues

“…We first assessed the activity of MVC with these dosing conditions in activated peripheral blood mononuclear cells (PBMCs) and other cellular models for preclinical evaluation in a mucosal environment, including immature dendritic cells (iDCs) and monocyte-derived macrophages (MDMs). 8 We observed different susceptibility to infection in the three models with higher levels of p24 in culture supernatant after 14 days of culture in PBMCs (33.29 -1.43 ng/ml) compared with MDMs (12.77 -0.73 ng/ml) and iDCs (1.27 -0.60 ng/ml).…”

“…We first assessed the activity of MVC with these dosing conditions in activated peripheral blood mononuclear cells (PBMCs) and other cellular models for preclinical evaluation in a mucosal environment, including immature dendritic cells (iDCs) and monocyte-derived macrophages (MDMs). 8 We observed different susceptibility to infection in the three models with higher levels of p24 in culture supernatant after 14 days of culture in PBMCs (33.29 -1.43 ng/ml) compared with MDMs (12.77 -0.73 ng/ml) and iDCs (1.27 -0.60 ng/ml).With all three drug exposure times, a dose-response curve was obtained against HIV-1 BaL in activated PBMCs (Fig. 1a) and MVC was able to reach an IC 50 at low and decreasing nanomolar concentrations with increasing dosing times (9.93 -1.68 nM with a 3-h exposure, 5.00 -1.38 nM with a 24-h exposure, and 0.94 -0.12 nM after continuous exposure).…”

Microbicide Dosage Forms

“…Several models have been utilized to evaluate bioactivity of microbicide drug candidates as described by Shattock and Herrera (2013). Most cell-based models for activity are limited in their usefulness due to the requirement of significant dilution of the gel product because of its high viscosity.…”