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Characteristic changes in HIV reverse trancriptase sequence at sites encoding known CTL epitopes at a population level

Mallal, S., Moore, C., John, M., James, I., Nolan, D., Sayer, D. and Witt, C. (2000) Characteristic changes in HIV reverse trancriptase sequence at sites encoding known CTL epitopes at a population level. In: XIII International AIDS Conference, 9 - 14 July 2000, Durban, South Africa


BACKGROUND: Nonsynonymous (NS) mutations in HIV reverse transcriptase(RT) sequence encoding HLA class I restricted CTL epitopes that lead to viral escape from host CTL responses have been described within individuals.The frequency and importance of CTL escape mutation has not been defined at a population level.

METHODS: 351 HIV-1 infected patients, with known HLA class I genotype and RT sequence were studied.Multiple logistic regression models were used to analyse associations between HLA class I alleles and NS mutations in RT sequence compared with the population consensus sequence,which differed from the clade B reference sequence WEAU (U21135) at four sites.

RESULTS: There was a strong association between HLA B51 and the presence of a NS mutation at position 135 of RT, which is an anchor residue of a known B51 restricted CTL epitope (p = 0.0001, OR = 56).In particular, all individuals with the B*5101 subtype had an I to T (79%) or V (21%) mutation at position 135. These mutations are known to markedly reduce B*5101 binding to an epitope.There appeared to be an association with the presence of B7 (p = 0.04,OR = 2) but this was abrogated by adjustment for all putative B7-associated escape mutations at other sites. Hence, NS mutation at position 135 was associated with a compensatory mutation at position 162 of RT. When position 162 (which is within a known B7-restricted CTL epitope) was examined,there was a strong association with B7 (p > 10-8, OR = 7). There was also a weaker association with B51 (p = 0.03,OR = 3) until adjustment for mutation at 135 was made. Conc: These results suggest that the phenomenon of CTL escape mutation of HIV is common and evident at a population level.Furthermore,CTL escape mutation at position 135 of reverse transcriptase may induce compensatory mutations at position 162 and vice versa.As with characteristic antiretroviral drug induced resistance mutations,knowledge of characteristic CTL escape mutations may prove useful in predicting viral dynamics in individuals

Item Type: Conference Paper
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