Selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug naive people
Simon Collins and Polly Clayden, HIV i-Base
Dr Garcia-Lerma’s group evaluated the replication capacity and relative replication fitness of recombinant viruses carrying reverse transcriptase (RT) sequences with the unusual mutations 215D, 215C or 215S derived from treatment-naïve individuals .
The investigators found that all viruses carrying the 215D, 215C or 215S replicated as efficiently as HIV-1 wild-type viruses but analysis of relative replicative fitness showed differences of fitness amongst them. Fitness of both 215D and 215C was higher than that of 215S in viruses that also had the 41L and/or 210W mutations, in contrast to viruses lacking the 41L and/or the 210W when fitness of 215S was higher than 215D/C.
They reported that these findings could explain the frequent association of 215D/C but not 215S with 41L and/or W observed in vivo. These mutations differ from 215Y by a single nucleotide change and are believed to represent revertants of the zidovudine (ZDV) selected T215Y in viruses that carry additional ZDV-resistance mutations. They speculated that reversion of 215Y may be a stepwise process in which several intermediates may be involved and in which the RT background may favour specific intermediates. In addition they suggest that the fitness gain conferred by the 215S mutation in the absence of other ZDV -selected mutations may represent a late reversion event from 215Y.They concluded that ‘efficient replication of all three intermediates suggests that they are stable mutations that persist in drug-na¥ve persons.’
The same group presented a second report in which they examined the prevalence of these mutations in 603 treatment-na¥ve, recently diagnosed persons, in which they found that 20 (3.3%) people had these mutations .
Their findings demonstrate that the prevalence of HIV-1 with unusual amino acids at codon 215 is substantial in treatment na¥ve persons. These are fit viruses that have WT phenotypes but show increased ability for selecting the 215Y mutation. The investigators concluded that ‘These findings may have clinical implications on the long-term efficacy of regimens containing ZDV in patients infected with these viruses.’
- Garcia- Lerma JG et al – Fitness analysis of viruses with unique T215D/C/S mutations from treatment-naive persons: implications on persistence in vivo and mechanisms of reversion of T215Y. Antiviral Therapy 2001; 6 (Supplement1):19. Abstract 22
- Garcia-Lerma JG et al – Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons. Antiviral Therapy 2001; 6 (Supplement1):19. Abstract 23