Spectrum of Activity of Raltegravir and Dolutegravir Against Novel Treatment-Associated Mutations in HIV-2 Integrase: A Phenotypic Analysis Using an Expanded Panel of Site-Directed Mutants

Author:

Smith Robert A12,Wu Vincent H12,Song Jennifer12,Raugi Dana N12,Diallo Mbaye Khardiata3,Seydi Moussa3,Gottlieb Geoffrey S124

Affiliation:

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

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.

Funder

National Institute of Allergy and Infectious Diseases

National Institutes of Health

University of Washington Center for AIDS Research

University of Washington Royalty Research Fund

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Immunology and Allergy

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