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

Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs r aises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, recently diagnosed HIV-1-infected persons,we identi fied a distinct group of viruses that have mutations at codon 215 of the re verse transcriptase (RT) gene that are different from either the wild-type (WT) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 2 15D/C/S and were found in 20 patients (3.3%). The 215D, 215C, and 215S muta tions 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 ha ve WT susceptibility to AZT, and all replicated efficiently as WT HIV-1(T21 5). 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 o f the RT background in the selection of these revertants. In vitro selectio n with AZT showed that HIV-1(215D) and HIV-1(215C) acquired 215Y more rapid ly than did WT HIV-1(T215), likely reflecting the need for only 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutation s at codon 215 replicate efficiently, have WT susceptibility, and are commo nly found in treatment-naive persons. The increased ability for selecting r esistance mutations defines this class of WT HIV-1 and highlights the highe r potential of these viruses to compromise the efficacy of antiretroviral t herapy.