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

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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) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 215D/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-1T215. However, differences in fitness among HIV-1215D, HIV-1215C, and HIV-1215S 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-1215D and HIV-1215C acquired 215Y more rapidly than did WT HIV-1T215, likely reflecting the need for only 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.

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