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The influence of host HLA on antiretroviral drug resistance mutation in HIV-1

Moore, C., John, M., James, I. and Mallal, S. (2002) The influence of host HLA on antiretroviral drug resistance mutation in HIV-1. In: 9th Conference on Retroviruses and Opportunistic Infections, 24 - 28 February 2002, Seattle, U.S.A.

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Background: Antiretroviral treatment (ART) to induced mutations in HIV-1 reverse transcriptase (RT) and protease that allow viral escape from drug suppression are well characterised. Similarly, host CTL responses select viral variants that can escape CTL responses. We have shown in a large population study, that CTL escape mutations are evident as HLA allele-specific mutations. We examined the hypothesis that selection pressures of both host HLA-restricted CTL responses and ART interact at specific sites, causing variable susceptibility to drug resistance mutation between HLA-diverse individuals.

Methods: 492 subjects with antiretroviral drug exposure, HLA-A and -B typing, pre- and post-ART RT(20-228) and protease(1-99) sequences over 2303 patient-years were studied. Multivariate logistic regression models were used to analyse associations between the development of ART-resistance mutations (as the outcomes) and ART (as covariates). We then analysed the effects of HLA alleles in these models.

Results: Associations between ZDV, 3TC, ddI, ddC, ABC, NVP, EFV, IDV, RTV, SQV, NFV, and one or more of their corresponding, known primary and secondary drug resistance mutations were demonstrable using this population-based approach (e.g. M184V in RT, was associated with use of 3TC(OR=69, p<0.001) and L90M in protease was associated with use of NFV [OR=3.1, p=0.003]). At other sites (46 RT and 12 protease residues) drug exposures decreased risk of mutation. In models incorporating HLA alleles, there were 57 residues in RT and 33 in protease at which mutation was associated with specific HLA-A and -B alleles (p<0.05). Like drug resistance mutations, HLA-specific mutations (putative CTL escape mutations) were site-specific, associated with stereotypic amino acid substitutions and secondary mutations. At 8 RT and 7 protease drug mutation sites, we detected HLA associations independently increasing or decreasing the risk of mutation (e.g., T215Y in RT was associated with ZDV [OR=3.7, p<0.001] and HLA-B7 [OR=2.3, p=0.007], but was less likely in those with HLA-B13 [OR=0.2, p=0.03]). In protease, V82A/T/F was associated with IDV (OR=4.3, p<0.001) and HLA-A2 (OR=5.4, p=0.002).

Conclusions: Knowledge of characteristic HLA-specific effects on viral sequence, including on drug resistance mutations may help explain variable susceptibility to drug resistance and be useful for individualisation of HIV therapy.

Item Type: Conference Item
Murdoch Affiliation(s): Centre for Clinical Immunology and Biomedical Statistics
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