Robert A Smith1,2, Vincent H Wu1,2, Jennifer Song1,2, Dana N Raugi1,2, Khardiata Diallo Mbaye3, Moussa Seydi3, Geoffrey S Gottlieb1,2,4. 1. Center for Emerging and Reemerging Infectious Diseases, University of Washington, Seattle, Washington, USA. 2. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA. 3. Service des Maladies Infectieuses et Tropicales, Centre Hospitalier National Universitaire de Fann, Dakar, Senegal. 4. Department of Global Health, University of Washington, Seattle, Washington, USA.
Abstract
BACKGROUND: Integrase inhibitors (INIs) are a key component of antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. Although INI resistance pathways are well-defined for HIV-1, mutations that emerge in HIV-2 in response to INIs are incompletely characterized. METHODS: We performed systematic searches of GenBank and HIV-2 drug resistance literature to identify treatment-associated mutations for phenotypic evaluation. We then constructed a library of 95 mutants of HIV-2ROD9 that contained single or multiple amino acid changes in the integrase protein. Each variant was tested for susceptibility to raltegravir and dolutegravir using a single-cycle indicator cell assay. RESULTS: We observed extensive cross-resistance between raltegravir and dolutegravir in HIV-2ROD9. HIV-2-specific integrase mutations Q91R, E92A, A153G, and H157Q/S, which have not been previously characterized, significantly increased the half maximum effective concentration (EC50) for raltegravir when introduced into 1 or more mutational backgrounds; mutations E92A/Q, T97A, and G140A/S conferred similar enhancements of dolutegravir resistance. HIV-2ROD9 variants encoding G118R alone, or insertions of residues SREGK or SREGR at position 231, were resistant to both INIs. CONCLUSIONS: Our analysis demonstrates the contributions of novel INI-associated mutations to raltegravir and dolutegravir resistance in HIV-2. These findings should help to improve algorithms for genotypic drug resistance testing in HIV-2-infected individuals.
BACKGROUND: Integrase inhibitors (INIs) are a key component of antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. Although INI resistance pathways are well-defined for HIV-1, mutations that emerge in HIV-2 in response to INIs are incompletely characterized. METHODS: We performed systematic searches of GenBank and HIV-2 drug resistance literature to identify treatment-associated mutations for phenotypic evaluation. We then constructed a library of 95 mutants of HIV-2ROD9 that contained single or multiple amino acid changes in the integrase protein. Each variant was tested for susceptibility to raltegravir and dolutegravir using a single-cycle indicator cell assay. RESULTS: We observed extensive cross-resistance between raltegravir and dolutegravir in HIV-2ROD9. HIV-2-specific integrase mutations Q91R, E92A, A153G, and H157Q/S, which have not been previously characterized, significantly increased the half maximum effective concentration (EC50) for raltegravir when introduced into 1 or more mutational backgrounds; mutations E92A/Q, T97A, and G140A/S conferred similar enhancements of dolutegravir resistance. HIV-2ROD9 variants encoding G118R alone, or insertions of residues SREGK or SREGR at position 231, were resistant to both INIs. CONCLUSIONS: Our analysis demonstrates the contributions of novel INI-associated mutations to raltegravir and dolutegravir resistance in HIV-2. These findings should help to improve algorithms for genotypic drug resistance testing in HIV-2-infected individuals.
Authors: Robert A Smith; Dana N Raugi; Vincent H Wu; Christopher G Zavala; Jennifer Song; Khardiata Mbaye Diallo; Moussa Seydi; Geoffrey S Gottlieb Journal: Antimicrob Agents Chemother Date: 2019-04-25 Impact factor: 5.191
Authors: Selly Ba; Dana N Raugi; Robert A Smith; Fatima Sall; Khadim Faye; Stephen E Hawes; Papa Salif Sow; Moussa Seydi; Geoffrey S Gottlieb Journal: Clin Infect Dis Date: 2018-10-30 Impact factor: 9.079
Authors: Robert A Smith; Dana N Raugi; Charlotte Pan; Matthew Coyne; Alexandra Hernandez; Brad Church; Kara Parker; James I Mullins; Papa Salif Sow; Geoffrey S Gottlieb Journal: PLoS One Date: 2012-09-18 Impact factor: 3.240
Authors: Joana Cavaco-Silva; Ana Abecasis; Ana Cláudia Miranda; José Poças; Jorge Narciso; Maria João Águas; Fernando Maltez; Isabel Almeida; Isabel Germano; António Diniz; Maria de Fátima Gonçalves; Perpétua Gomes; Celso Cunha; Ricardo Jorge Camacho Journal: PLoS One Date: 2014-03-28 Impact factor: 3.240