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60 Simon Mallal Ctr for Clin Immunology and Biomed Statistics, Royal Perth Hosp, Australia |
Background: Human leukocyte antigens (HLA) are the most polymorphic human proteins, with over 1300 distinct alleles defined to date. At the individual level, the inheritance of specific HLA alleles shape the immune response in a manner that is analogous to antiretroviral drugs, in that each allele provides a specific selective pressure which may induce characteristic HIV escape mutations. At the population level, this extreme HLA diversity acts as a significant impediment to the uncontrolled spread of pathogenic viruses. Importantly, HLA diversity has evolved in the presence of different endemic and epidemic pathogens in different ethnic/racial populations, which is reflected in differing frequency of HLA alleles according to ethnic/racial origin; and in non-random frequency distribution of HLA within these populations. HIV has an almost unprecedented ability to adapt rapidly to HLA-restricted immune responses both within an individual and at a population level. This capacity for HIV genetic mutation and recombination is so great that it is possible to analyse HLA-viral mutation associations at the single amino acid level. However, the likelihood of HIV adaptation is influenced by a number of factors. First, the magnitude of the genetic hurdle to escape. Second, the cost to viral fitness/replicative success. Third, as with drug resistance, the risk of selection of escape variants is likely to be greatest in the presence of intermediate levels of selective pressure and ongoing viral replication.
