HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703
Matthews, P.C.; Adland, E.; Listgarten, J.; Leslie, A.; Mkhwanazi, N.; Carlson, J.M.; Harndahl, M.; Stryhn, A.; Payne, R.P.; Ogwu, A.; Huang, K-Hsiang.Gary.; Frater, J.; Paioni, P.; Kloverpris, H.; Jooste, P.; Goedhals, D.; van Vuuren, C.; Steyn, D.; Riddell, L.; Chen, F.; Luzzi, G.; Balachandran, T.; Ndung'u, T.; Buus, Søren.; Carrington, M.; Shapiro, R.; Heckerman, D.; Goulder, P.J.R.
Journal of Immunology 186(10): 5675-5686
2011
ISSN/ISBN: 0022-1767 PMID: 21498667 DOI: 10.4049/jimmunol.1003711Document Number: 221271
The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*741 is associated with favorable viremic control in extended southern African cohorts of >21 C-clade–infected subjects. We present evidence that HLA-A*741 operates an effect that is independent of HLA-B*573, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*741 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*741 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*741–restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*741–restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*573.