A zidovudine-resistant simian immunodeficiency virus mutant with a Q151M mutation in reverse transcriptase causes...

The simian immunodeficiency virus (SIV)-newborn rhesus macaque model of AIDS can be used to study directly the virulence of viral mutants which are resistant to antiviral drugs. A viral mutant called SIVmac79A6.1, isolated from an SIV-infected macaque after prolonged zidovudine treatment, was found to have a double-base-pair change at codon 151 of reverse transcriptase, resulting in a glutamine to methionine substitution (Q151M). This mutation was associated with more than 100-fold increased resistance to zidovudine and low-level cross-resistance to other dideoxynucleoside analogs. To determine whether this Q151M mutation affects viral virulence, four newborn macaques were inoculated intravenously with a biological clone of this drug-resistant SIVmac79A6.1 mutant; two of these animals were also treated orally with zidovudine. All four animals showed persistent viremia, and two of the four animals developed fatal immunodeficiency at 3 and 8 months of age, respectively. The remaining two animals had CD4+ T-cell depletion and clinical symptoms of AIDS at 22 months. No phenotypic or genotypic reversion of virus to the wild type could be detected in any of the four animals. These results demonstrate that the Q151M mutation in SIV reverse transcriptase does not reduce viral virulence.