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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
Treatment with a potent antiviral introduces a strong genetic bottleneck. During therapy failure with resistance development, the virus passes through this bottleneck and typically regains its original virus load. We have used the heteroduplex tracking assay to follow the effects of a ritonavir-induced bottleneck in a cohort of subjects with low CD4 cell counts who had ritonavir added to their pre-existing therapy (Abbott Trial M94-247). The composition and turnover of three regions of the HIV-1 genome were monitored during the development of resistance: the pro gene, the V1/V2 region of env, and the V3 region of env. Virus rebound was associated with the appearance of resistance mutations in protease. Typically, there was a sequential replacement of viral protease species over a 6–12-month period. However, in some cases a small amount of the wild-type pro persisted as a minor species. V1/V2 and V3 went through dramatic homogenizations in passing through the bottleneck, being represented by a single species at the point of virus load rebound. In half of the subjects, the single species present at rebound was a minor species prior to rebound. We interpret this result to suggest that the initial resistance marker is typically linked to a low abundance env species, or that other selective pressures on env created by the introduction of drug allowed the outgrowth of this minor variant. The continued evolution of pro to add additional resistance mutations is accompanied by a rediversification of env. In some subjects the pre-existing env species reappeared, while in others new species evolved. The reappearance of old env species during further resistance evolution suggests that recombination between pro and env occurs at a high rate. In several cases there was a transient improvement in CD4 cell counts that extended beyond virus load rebound. The subsequent drop in CD4 cell count appeared to be correlated with a change in env populations. This result suggests either that a more pathogenic variant of HIV-1 evolved, or that this change in env population was a result of the decline in the improved host immune response associated with the transient CD4 cell increase.
PRESENTING AUTHOR: R Swanstrom
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