5th International Workshop on HIV Drug Resistance & Treatment Strategies


4-8 June 2001, Scottsdale, Arizona

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[TITLE:] INCREASED ABILITY FOR SELECTION OF ZIDOVUDINE RESISTANCE IN A DISTINCT CLASS OF WILD-TYPE HIV-1 FROM DRUG-NAÏVE PERSONS

[AUTHOR(S):] JG García-Lerma1, S Nidtha1, K Blumoff1, H Weinstock2 and W Heneine1
1 HIV and Retrovirology Branch, Centers for Disease Control and Prevention, Atlanta, Ga., USA; and 2 Prevention Services Research Branch, Centers for Disease Control and Prevention, Atlanta, Ga., USA
Antivir Ther. 2001;6 Suppl 1:19

The T215Y (ACC–TAC) mutation is a major mutation associated with zidovudine resistance. While transmission of HIV-1T215Y has been documented, HIV-1 with a distinct set of mutations at codon 215, such as 215D and 215C, has also been seen in treatment-naïve persons. These mutations differ by one nucleotide from 215Y and are thought to represent revertants of 215Y. We examined the prevalence of these mutations in 603 treatment-naïve, recently diagnosed HIV-1-infected persons identified between 1997–1999 in 10 US cities. We found that 20 (3.3%) persons had these mutations. Eight persons had 215D, six had 215C, four had 215S, one had 215E and one had 215I. Phenotypic analysis showed that 19 viruses had wild-type (WT) susceptibility to zidovudine and other nucleoside analogues. Low level (6.4-fold) resistance to zidovudine was observed only in one patient who had a 215I mutation and a deletion at position 67. We analysed the impact of 215D and 215C on both replication capacity and rate of acquisition of zidovudine resistance. Five patient-derived recombinant viruses carrying 215C or 215D alone or in association with M41L and/or L210W were investigated. The effect of 215C and 215D was also evaluated in HIV-1HXB2. All seven viruses replicated as efficiently as control WT HIV-1T215 in the absence, and in the presence, of zidovudine, which may explain their persistence in vivo. Selection experiments with zidovudine in vitro showed that all viruses with 215C and 215D had increased rates of acquisition of 215Y. Evolution from 215 C/D to 215Y was seen after a mean of 28 days in culture (range 18–37 days). In contrast, selection of zidovudine resistance in control WT viruses was observed after a mean of 63 days (range 53–81 days), and involved mutations other than 215Y. Our data demonstrate that the prevalence of HIV-1 with unusual amino acids at codon 215 is substantial in treatment-naïve persons. These viruses are fit and represent a distinct class of HIV-1 that have WT phenotypes but show increased ability for selecting the 215Y mutation. These findings may have clinical implications on the long-term efficacy of regimens containing zidovudine in patients infected with these viruses.

PRESENTING AUTHOR: JG García-Lerma

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