HLA-A*7401-Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B*5703
- Philippa C. Matthews ,
- Emily Adland ,
- Jennifer Listgarten ,
- Alasdair Leslie ,
- Nompumelelo Mkhwanazi ,
- Jonathan M. Carlson ,
- Mikkel Harndahl ,
- Anette Stryhn ,
- Rebecca P. Payne ,
- Anthony Ogwu ,
- Kuan-Hsiang Gary Huang ,
- John Frater ,
- Paolo Paioni ,
- Henrik Kolverpris ,
- Pieter Jooste ,
- Dominique Goedhals ,
- Cloete van Vuuren ,
- Dewald Steyn ,
- Lynn Riddell ,
- Fabian Chen ,
- Graz Luzzi ,
- Thambiah Balachandran ,
- Thumbi Ndung'u ,
- Soren Buus ,
- Mary Carrington ,
- Roger Shapiro ,
- David Heckerman ,
- Philip J. R. Goulder
The Journal of Immunology |
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*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade–infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, 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*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 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*7401–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*7401–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*5703.