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Conference
"Differences Among HIV Subtypes in Regard to Drug Resistance" Prof. Mark Wainberg (biography) English - 2003-03-30 - 29 minutes
Summary : HIV Drug resistance: Novel Mutational profiles in Non-Subtype B Infections
Despite the predominance and rising expansion of HIV-1 non-B infections (class A through J) worldwide, there is limited information on the effects of subtype genomic diversity on viral responses to antiretroviral therapy and on the development of resistance to these drugs. Non-B subtypes differ by 10-20% in the reverse transcriptase (RT) and protease (PR) genes, in addition to 30-40% sequence divergence in viral envelope genes. Indeed, recent studies have identified novel mutations in non-B clades that are not presently identified by current genotypic testing and virtual phenotypic algorithms. Moreover, differences in rates of replication, referred to as viral fitness, may have a considerable impact on both drug and development of resistance. An example is a previously unrecognized V106M mutation that is selected by efavirenz (EFV) among the clade C but not the clade B viruses. This is due to the fact that subtype C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG ATG) after selection with EFV. In contrast, subtype, B viruses encode, V through a GTA codon at position 106 that is most likely to mutate to GCA (A), which encodes resistance to nevirapine (NVP). Moreover, the V106M but not the V106A substitution confers broad cross-resistance to all currently approved NNRTIs.
We have also compared the evolutionary potential of wild-type and M184V-containing variants of HIV-1 under conditions of selective drug pressure. To assess the effect of the M184V substitution on the development of resistance-associated mutations, we grew viruses of either subtype B or C origin, containing M184V or not, in the presence of amprenavir (APV) and efavirenz (EFV) in peripheral blood mononuclear cells (PBMCs). In all our selections, subtype C viruses showed a replicative advantage compared to subtype B viruses. For both subtypes B and C, we found a 5 to 7 week lag in development of phenotypic resistance to either APV or EFV in the M184V-containing viruses compared to their wild-type (WT) counterparts. Genotypic analysis revealed some differences in the resistance-conferring mutations in the different subtypes, and the appearance of these mutations was also delayed in the M184V-containing variants compared to viruses not containing M184V. These genotypic data are in agreement with previous studies showing that M184V does not limit the evolutionary potential of HIV. However M184V can influence the types of resistance-conferring mutations that arise in tissue culture selection for both subtype B and C viruses as well as the rapidity of accumulation of relevant resistance-conferring mutations.
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