Characteristic Non-synonymous mutation in HIV reverse transcriptase sequence encoding an HLA-B7-restricted CTL epitope is associated with increased viral load
John, M., Moore, C., James, I. and Mallal, S. (2001) Characteristic Non-synonymous mutation in HIV reverse transcriptase sequence encoding an HLA-B7-restricted CTL epitope is associated with increased viral load. In: 8th Conference on Retroviruses and Opportunistic Infections, 4 - 8 February 2001, Chicago, IL
Background: Non-synonymous (NS) mutations in HIV sequences encoding HLA class I-restricted CTL epitopes that lead to viral escape from host CTL responses have been documented in individuals. More recently, we have shown that characteristic mutations in the HIV reverse transcriptase (RT) sequence encoding known and putative CTL epitopes are evident at a population level. For example, the presence of HLA-B7 in the Western Australian HIV Cohort Study is strongly associated with NS mutation at position 162 of HIV R, -a known HLA- B7-restricted CTL epitope. Similarly, HLA-B51 is strongly associated with NS mutation at position 135 of HIV RT, which encodes an anchor residue of a known HLA-B51-restricted CTL epitope. We sought to determine the effects of these mutations on HIV viral load.
Methods: 351 HIV-1-infected patients who had undergone HLA class I typing, serial HIV RT sequencing and viral load determinations were studied. Multiple logistic regression models were used to analyse associations between HLA class I alleles and NS mutation in the HIV RT sequence compared with population consensus sequence, which only differed from the clade B reference sequence WEAU (U21135) at four sites. Pre- antiretroviral treatment viral loads (at the time of the RT sequencing) in patients with and without a mutation at position 162 were compared.
Results: Among HLA-B7 individuals, the mean pre-treatment viral load was 5.17+0.246 log cps/ml (mean+SEM) in those with a mutation at position 162 compared with 4.51+0.184 log cps/ml in those who did not have the mutation (p = 0.0373, t-test). Viral load in HLA-B7 individuals without the mutation was not significantly different from viral load in non-HLA-B7 individuals. The effect of HLA-B51-associated mutation on viral load could not be determined as all patients with HLA-B51 had a mutation at position 135.
Conclusions: Mutation in a known HLA-B7-restricted CTL epitope in HIV RT occurs commonly in HLA-B7 individuals and is associated with higher pre-treatment viral load, suggesting that it is an adaptive mutation that allows escape from host CTL responses. As with some antiretroviral drug-associated mutations, knowledge of characteristic CTL escape mutations may prove useful in predicting viral load.
|Publication Type:||Conference Paper|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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