A ZIDOVUDINE-RESISTANT SIMIAN IMMUNODEFICIENCY VIRUS MUTANT WITH A Q151M MUTATION IN REVERSE-TRANSCRIPTASE CAUSES AIDS IN NEWBORN MACAQUES

The simian immunodeficiency virus (SIV)-newborn rhesus macaque model o f AIDS can be used to study directly the virulence of viral mutants wh ich are resistant to antiviral drugs. A viral mutant called SIVmac79A6 .1, isolated from an SIV-infected macaque after prolonged zidovudine t reatment, was found to have a double-base-pair change at codon 151 of reverse transcriptase, resulting in a glutamine to methionine substitu tion (Q151M). This mutation was associated dth more than 100-fold incr eased resistance to zidovudine and low-level cross-resistance to other dideoxynucleoside analogs. To determine whether this Q151M mutation a ffects viral virulence, four newborn macaques were inoculated intraven ously with a biological clone of this drug-resistant SIVmac79A6.1 muta nt; two of these animals were also treated orally with zidovudine. All four animals showed persistent viremia, and two of the four animals d eveloped fatal immunodeficiency at 3 and 8 months of age, respectively . The remaining two animals had CD4(+) T-cell depletion and clinical s ymptoms 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. T hese results demonstrate that the Q151M mutation in SIV reverse transc riptase does not reduce viral virulence.