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Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons.

Proceedings of the National Academy of Sciences 2001;98:13907-13912.

Garcia-Lerma JG, Nidtha S, Blumoff K, Weinstock H, Heneine W.

Abstract

Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naïve, recently diagnosed HIV-1-infected persons, we identified a distinct group of viruses that have mutations at codon 215 of the reverse transcriptase(RT) gene that are different from either the wild-type (WT) Tor the zidovudine (AZT)-selected T215Y/F. These mutations included215D/C/S and were found in 20 patients (3.3%). The 215D, 215C,and 215S mutations differ from 215Y by a 1-nt change compared with 2 nt for the WT T215 and likely represent revertants of 215Y.These viruses all were found to have WT susceptibility to AZT,and all replicated efficiently as WT HIV-1_T215. However, differences in fitness among HIV-1_215D, HIV-1_215C, and HIV-1_215S were seen when RT backgrounds were changed, demonstrating a role of the RT background in the selection of these revertants. In vitro selection with AZT showed that HIV-1_215D and HIV-1_215C acquired 215Y more rapidly than did WT HIV-1_T215, likely reflecting the need foronly 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutations at codon 215 replicate efficiently, have WT susceptibility, and are commonly found in treatment-naïve persons. The increased ability for selecting resistance mutations defines this class of WT HIV-1 and highlights the higher potential of these viruses to compromise the efficacy of antiretroviral therapy.