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 raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, 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-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 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-naive 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.
Garcia-Lerma
J G
JG
HIV and Retrovirology Branch, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. GGarcia-Lerma@cdc.gov
Nidtha
S
S
Blumoff
K
K
Weinstock
H
H
Heneine
W
W
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D004279:DNA, Viral; D016049:Didanosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011995:Recombination, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018119:Stavudine / Q000494:pharmacology; D014779:Virus Replication / Q000235:genetics; D016047:Zalcitabine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use; D000099227:Abacavir
D019380:Anti-HIV Agents; D004279:DNA, Viral; D016049:Didanosine; D015224:Dideoxynucleosides; D054303:HIV Reverse Transcriptase; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D016047:Zalcitabine; D015215:Zidovudine; D000099227:Abacavir