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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

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...

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Published in:The Journal of infectious diseases 2022-08, Vol.226 (3), p.497-509
Main Authors: Smith, Robert A, Wu, Vincent H, Song, Jennifer, Raugi, Dana N, Diallo Mbaye, Khardiata, Seydi, Moussa, Gottlieb, Geoffrey S
Format: Article
Language:English
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Summary: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. Mutations that are unique to HIV-2 or that rarely appear in HIV-1–infected patients can contribute to integrase inhibitor resistance. Our findings will help to refine the algorithms used for detecting emergent drug resistance in people living with HIV-2.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiac037