Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 65, Issue 12, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01167-21
Keywords
EFdA; HIV drug resistance; HIV-1 reverse transcriptase; NRTIs; inhibitors; islatravir
Categories
Funding
- NIH [R37 AI076119, T32 GM008367, F31 AI155158-01A1]
- Nahmias-Schinazi Distinguished Chair in Research
- Emory Integrated Genomics Core (EIGC) - Emory University School of Medicine
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000454]
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The study demonstrates that EFdA exhibits exceptional potency against HIV-1, with M184V and A114S/M184V identified as key mutations contributing to EFdA resistance. These mutations show higher sensitivity to tenofovir and are suitable for use in treatment of naive, AZT, FTC/3TC, and tenofovir-treated patients.
4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA, MK-8591, islatravir) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with exceptional potency against wild-type (WT) and drug-resistant HIV-1 in phase III clinical trials. EFdA resistance is not well characterized. To study EFdA resistance patterns that may emerge in naive or tenofovir (TFV)-, emtricitabine/lamivudine (FTC/3TC)-, or zidovudine (AZT)-treated patients, we performed viral passaging experiments starting with WT, K65R, M184V, or D67N/K70R/T215F/K219Q HIV-1. Regardless of the starting viral sequence, all selected EFdA-resistant variants included the M184V reverse transcriptase (RT) mutation. Using recombinant viruses, we validated the role for M184V as the primary determinant of EFdA resistance; none of the observed connection subdomain (R358K and E399K) or RNase H domain (A502V) mutations significantly contributed to EFdA resistance. A novel EFdA resistance mutational pattern that included A114S was identified in the background of M184V. A114S/M184V exhibited higher EFdA resistance (similar to 24-fold) than either M184V (similar to 8-fold) or A114S alone (similar to 2-fold). Remarkably, A114S/M184V and A114S/M184V/A502V resistance mutations were up to 50-fold more sensitive to tenofovir than was WT HIV-1. These mutants also had significantly lower specific infectivities than did WT. Biochemical experiments confirmed decreases in the enzymatic efficiency (k(cat)/K-m) of WT versus A114S (2.1-fold) and A114S/M184V/A502V (6.5-fold) RTs, with no effect of A502V on enzymatic efficiency or specific infectivity. The rather modest EFdA resistance of M184V or A114S/M184V (8- and 24-fold), their hypersusceptibility to tenofovir, and strong published in vitro and in vivo data suggest that EFdA is an excellent therapeutic candidate for naive, AZT-, FTC/3TC-, and especially tenofovir-treated patients.
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