Role of Genetic Diversity amongst HIV-1 Non-B Subtypes in Drug Resistance: A Systematic Review of Virologic and Biochemical Evidence

The genetic diversity of HIV-1 has required its classification into types and subtypes. There is controversyas to how and to what extent genetic diversity may affect the emergence of antiretroviral drugresistance in HIV-1 subtypes other than B. To better understand the impact of genetic diversity (representedby different HIV-1 subtypes) on resistance to reverse transcriptase and protease inhibitordrugs, a systematic review was conducted on virologic and biochemical evidence obtained from workwith non-B HIV-1 subtypes. We searched 11 databases and retrieved 3,486 citations on all aspects ofnon-B subtype-related resistance research. Twenty-seven studies with virologic and/or biochemicaldata met the eligibility criteria for our systematic review. Nineteen studies were found that reportedphenotypes in non-B subtypes (304 from naive isolates and 242 from drug-exposed isolates) and 11 studiesthat used molecular biology techniques to study non-B resistance to antiretroviral drugs. Comparedto the NL4-3 laboratory strain, lower baseline susceptibilities of recombinant A/G subtype virusto protease inhibitors were observed and a substantial proportion of subtype C isolates displayedhigher IC50 at baseline for atazanavir. Some A/G isolates were found to have reduced susceptibility toabacavir. Mutations not typical of B subtypes include the reverse transcriptase mutation V106M andthe protease mutations M89I/V and N83T. Virologic and biochemical data suggest that K65R is morelikely to emerge in subtype C HIV-1. There is evidence to suggest differential effects of other mutationsaccording to subtype, e.g. the protease inhibitor mutations I93L and M89I/V. Importantly, the mostwidely used commercial phenotyping systems do not take into account gag variations among naturalisolates, which could limit the accuracy of measured susceptibility. Enzymatic and virologic datasupport the concept that naturally occurring polymorphisms in different non-B subtypes can affectthe susceptibility of HIV-1 to different antiretroviral drugs, the magnitude of resistance conferredby major mutations, and the propensity to acquire some resistance mutations. Tools may need tobe optimized to accurately measure drug susceptibility of non-B subtypes, especially for proteaseinhibitors.