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Development of Human Immunodeficiency Virus Type 1 Resistance to 4’-Ethynyl-2-Fluoro-2’-Deoxyadenosine (EFdA) Starting with Wild-Type or Nucleoside Reverse Transcriptase Inhibitor Resistant-Strains

Maria E. Cilento, Aaron B. Reeve, Eleftherios Michailidis, Tatiana V. Ilina, Eva Nagy, Hiroaki Mitsuya, Michael A. Parniak, Philip R. Tedbury, Stefan G. Sarafianos

Abstract: 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA, MK-8591, islatravir) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with exceptional potency against WT and drug-resistant HIV-1, in Phase III clinical trials. EFdA resistance is not well characterized. To study EFdA-resistance patterns as it may emerge in naïve or tenofovir- (TFV), emtricitabine/lamivudine- (FTC/3TC), or zidovudine- (AZT) treated patients we performed viral passaging experiments starting with wild-type, K65R, M184V, or D67N/K70R/T215F/K219Q HIV-1. Regardless the starting viral sequence, all selected EFdA-resistant variants included the M184V 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 (∼24-fold) than M184V (∼8-fold) or A114S alone (∼2-fold). Remarkably, A114S/M184V and A114S/M184V/A502V resistance mutations were up to 50-fold more sensitive to tenofovir than WT HIV-1. These mutants also had significantly lower specific infectivity than WT. Biochemical experiments confirmed decreases in the enzymatic efficiency (k cat /K m ) of WT vs. 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 naïve, AZT-, FTC/3TC, and especially tenofovir-treated patients.
Keywords: HIV / EFdA resistance / naïve / FTC/3TC / A502V / AZT / M184V / fold / Virus

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