HIV-1 Resistance to Islatravir/Tenofovir Combination Therapy in Wild-Type or NRTI-Resistant Strains of Diverse HIV-1 Subtypes

• Type of Material: Article
• Authors: Maria E. Cilento, Emory University; Xin Wen, Emory University; Aaron B. Reeve, University of Pittsburgh; Obiaara B. Ukah, University of Missouri; Alexa Snyder, Emory University; Ciro M. Carrillo, Emory University; Cole Smith, Emory University; Kristin Edwards, Emory University; Caludia C. Wahoski, Emory University; Deborah R. Kitzler, Emory University; Eiichi N. Kodama, Tohoku University; Hiroaki Mitsuya, Kumamoto University; Michael A. Parniak, University of Pittsburgh; Philip Tedbury, Emory University; Stefan Sarafianos, Emory University
• Language: English
• Date: 2023-09-25
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.3390%2Fv15101990
• Title of Journal or Parent Work: Viruses
• Volume: 15
• Issue: 10
• Start Page: 1990
• Grant/Funding Information: This research was funded by NIH grants R37 AI076119 and P30 AI050409 (Center for AIDS Research at Emory University) to S.G.S. and T32 GM008367 and F31 AI155158 (training funds for M.E.C.) and F31 AI172618 (training funds for A.A.S.). S.G.S. acknowledges funding from the Nahmias-Schinazi Distinguished Research Chair. This study was also supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine. Additional support was provided by the National Center for Advancing Translational Sciences of the NIH under award UL1TR000454.
• Keywords: drug resistance; EFdA; islatravir; nucleoside reverse transcriptase translocation inhibitors; Tenofovir; Nucleoside reverse transcriptase inhibitors
• Research Categories: Biology, Virology

Abstract

Tenofovir disoproxil fumarate (TDF) and islatravir (ISL, 4′-ethynyl-2-fluoro-2′-deoxyadensine, or MK-8591) are highly potent nucleoside reverse transcriptase inhibitors. Resistance to TDF and ISL is conferred by K65R and M184V, respectively. Furthermore, K65R and M184V increase sensitivity to ISL and TDF, respectively. Therefore, these two nucleoside analogs have opposing resistance profiles and could present a high genetic barrier to resistance. To explore resistance to TDF and ISL in combination, we performed passaging experiments with HIV-1 WT, K65R, or M184V in the presence of ISL and TDF. We identified K65R, M184V, and S68G/N mutations. The mutant most resistant to ISL was S68N/M184V, yet it remained susceptible to TDF. To further confirm our cellular findings, we implemented an endogenous reverse transcriptase assay to verify in vitro potency. To better understand the impact of these resistance mutations in the context of global infection, we determined potency of ISL and TDF against HIV subtypes A, B, C, D, and circulating recombinant forms (CRF) 01_AE and 02_AG with and without resistance mutations. In all isolates studied, we found K65R imparted hypersensitivity to ISL whereas M184V conferred resistance. We demonstrated that the S68G polymorphism can enhance fitness of drug-resistant mutants in some genetic backgrounds. Collectively, the data suggest that the opposing resistance profiles of ISL and TDF suggest that a combination of the two drugs could be a promising drug regimen for the treatment of patients infected with any HIV-1 subtype, including those who have failed 3TC/FTC-based therapies.