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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
BACKGROUND: It is well accepted that certain HIV-1 drug resistance mutations, particularly protease inhibitor mutations, also impair viral replication. However, it is unclear how much inherent variation in replication capacity exists among drug sensitive/naïve ‘wild-type’ viruses. Thus it is difficult to discern to what extent the reduced replication capacity seen in viruses with reduced susceptibility to antiretrovirals is related to the natural variation in the virus versus how much is directly caused by the accumulation of drug resistance mutations.
METHODS: Replication capacity was measured using a single replication cycle assay (PhenoSense HIV). Replication capacity of ‘wild-type’ viruses was compared to a well-characterized reference virus (NL4-3). This study compares the replication capacities of 49 viruses with no phenotypic drug resistances or resistance-associated mutations as determined by genotyping versus 112 viruses with phenotypic reductions in susceptibility to one or more drugs.
RESULTS: Viruses with ‘wild-type’ drug susceptibilities displayed a broad range of replication capacities (median=73%, IQ range: 47–89) compared to the control virus, NL4-3. By contrast, patient viruses with reduced susceptibility (n=112) to at least one drug had lower replication capacities (median=28%, IQ range: 11–46, P<0.001). In addition, viruses with hypersusceptibility (HS) to protease inhibitors (fold-change <0.4) also displayed reduced replication capacity (median=31% (HS) versus 40% (non-HS), P=0.06). Reverse transcriptase (RT) function was measured with an in vitro elongation assay and protease was evaluated for its ability to properly process the Gag protein as measured by Western blot analysis. All viruses without reduced susceptibility to any drug demonstrated normal levels of Gag cleavage by protease and <10% had impaired RT function, whereas 47% of viruses with resistance to at least one drug had impaired RT or protease function.
CONCLUSIONS: Replication capacity of ‘wild-type’ HIV-1, as measured in a single cycle assay, spanned a broad range , with a mean of 70% of the NL4-3 reference. This distribution is distinct from that observed in drug-resistant viruses. Reduced drug susceptibility, as well as protease inhibitor hypersusceptibility, is associated with reduced replication capacity. Major changes in replication capacity are correlated with significantly impaired RT and protease function.
PRESENTING AUTHOR: T Wrin
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