Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance
Year: 2023
Type: article
Abstract: Darunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in high drug concentrations that are achieved in vivo. Little is known about the de novo resistance pathway for DRV. We selected for resistance to high drug concentrations against 10 PIs and their structural precursor DRV. Mutations accumulated through two pathways (anchored by protease mutations I50V or I84V). Small changes in the inhibitor P1'-equivalent position led to preferential use of one pathway over the other. Changes in the inhibitor P2'-equivalent position determined differences in potency that were retained in the resistant viruses and that impacted the selected mutations. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high level of selective pressure that is attainable with fifth-generation PIs and how features of the inhibitor affect both the resistance pathway and the residual potency in the face of resistance.
Source: eLife
DOI: 10.7554/elife.80328
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Center for AIDS Research, University of North Carolina at Chapel Hill
Awards: G1079176756, G2262217435, HIV Evolution Defines Virus-Host/Drug Interactions In Viremic and Aviremic People, G311558797, G5900455136, G6915740730, G7011138146, G7366156696, Integration of Evolution to Avoid Resistance in Structure Based Drug Design, G9000033364, G9000240271, G9000311747, The University of North Carolina Center for AIDS Research, Cancer Center Support Grant, The Interdependency of Drug Resistance Evolution and Drug Design: HIV-1 Protease, G958207224
OpenAlex ID: W4324309755