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12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
BACKGROUND: HIV-1 reverse transcriptase (RT) amino acid position 215 is monomorphic for threonine (T) in the ‘wild-type’ virus population. Thymidine analogues such as zidovudine and stavudine select for drug resistant variants containing tyrosine (215Y) or phenylalanine (215F). Two nucleotide changes are required to substitute T by Y or F. Intermediate alleles containing single ‘forward’ mutations encoding for 215N/S/I are drug-sensitive. 215N/S/I variants can also appear as the result of single revertant mutations of T215Y/F when drug pressure is interrupted. Variants 215D/V/C/H/L generated by single revertant mutations of T215Y/F preserve the two ‘forward’ nucleotide changes from 215T. Our objective is to evaluate the emergence of T215 variants in (a) a large sequence database compiled from HIV-1 isolates submitted for routine antiretroviral drug resistance testing and (b) a small cohort of HIV-1-infected patients that participated in a structured treatment interruption study.
METHODS: A database of matched genotypes and phenotypes from over 1000 clinical longitudinal samples gathered from 1999 to 2003 was queried for samples containing T215Y or F (not mixed) at the first time point. Correlation between the presence of T215Y or F mutation at the first and the 215-mutant at the second time point was tested using logistic regression. Mean replication capacity (RC) of each 215 substitution was calculated from protease wild-type samples. Ten longitudinal plasma samples were part of a supervised structured treatment interruption study (Deeks et al., N Engl J Med. 2001 Feb 15;344(7):472-80).
RESULTS: Fifty-five longitudinal pairs of viruses were identified with T215Y (n=44) or T215F (n=11) at the first time point. Twenty-two of these viruses (20 T215Y and 2 T215F) showed complete replacement by the wild-type 215T virus at the second time point. Five viruses showed complete replacement by revertant mutants: 215Y by S, D, and C, 215F by S and V. Two of these five viruses showed a complete reversion to phenotypic susceptibility to all drugs and loss of drug-selected mutations at other positions in RT and protease, strongly suggesting an outgrowth of archival drug-sensitive viruses carrying a revertant codon at position 215. Twenty-eight viruses (21 T215Y and 7 T215F) showed complex mixtures of position 215. Mean RC was high for 215T, S, D, C (100, 120, 102, 98 respectively), and lower for 215V, L, I (62, 61, 40 respectively).
CONCLUSIONS: T215 revertants are common in HIV-1 patients. T215Y and F revert preferably to 215-codons that are one nucleotide different (Y215S/D/C, F215S/V). The relationship between the variant at the first time point and at the second time point supports the model that the RC of the various variants determines their relative presence in the archived virus pool and their subsequent emergence in the absence of selective pressure.
PRESENTING AUTHOR: C Chappey
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2003-07-08
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