Resistance to integrase strand transfer inhibitors

Division Of Basic Sciences - Nci

Investigators

Abstract

Integrase strand transfer inhibitors (INSTIs) are highly efficacious drugs that are becoming increasingly foundational to current antiretroviral regimens globally. However, virological failure to INSTI-containing regimens can occur in PWH in the absence of drug resistance mutations in integrase. Over the past few years, we have identified and characterized mutations in Env and NC that reduce the susceptibility of HIV-1 to INSTIs. The mutations in Env increase the efficiency of HIV-1 spread, thereby overwhelming the inhibitory activity of the INSTIs. Ongoing and future work will focus on determining the mechanism by which Env and NC mutations confer resistance to antiretrovirals, and whether, and under what conditions, these non-canonical drug resistance pathways occur in vivo. Importantly, in collaboration with clinical investigators, we have recently obtained evidence that NC mutations arise in association with virologic failure to INSTIs in PWH (which we presented in two talks at CROI 2025). We are also collaborating with chemists and structural biologists to develop third-generation INSTIs with improved potency and superior resistance profiles relative to approved second-generation INSTIs (e.g., dolutegravir and cabotegravir). This project has 3 specific aims: a) Identify and characterize non-canonical INSTI resistance pathways in cell culture, b) Identify and characterize non-canonical INSTI resistance pathways in PWH, and c) Contribute to the development of 3rd-generation INSTIs and define resistance pathways.