Inter-Continental Patterns of HIV-1 Control: HLA and the Quest for a T Cell Vaccine
Section snippets
Abstract
In light of the recent failure of the Merck T cell vaccine to elicit anti-HIV immunity, further characterisation of T cell responses is required.
The CD8+ T cell response is directed by the presentation of epitopes (viral peptide fragments) in association with HLA Class I molecules on the surface of infected cells. Thus, HLA genotype is a significant determinant of set-point viraemia, and of time to AIDS. HLA is also a strong selection force for HIV polymorphisms; the virus selects for escape
Method
- (1)
We studied viral sequences from >2800 patients in five continents, to identify the relationship between the prevalence of particular HLA alleles and the frequency of HLA-selected mutations.
- (2)
We identified locations of HLA-associated viral escape mutation in a cohort of 710 adults in South Africa, and compared these with sites at which there are differences between HIV-1 clades.
- (3)
We studied a UK cohort of 200 subjects from diverse ethnic backgrounds. We analysed viral sequences, viral load, and T
Results
- (1)
We demonstrated a strong correlation between the frequency of a given HLA allele and the prevalence of HIV mutations selected by this allele, demonstrating the significant evolutionary impact of HLA on HIV.
- (2)
We observed that sites of HLA-mediated selection overlap significantly with sites of inter-clade difference in HIV, showing that clade differences may, in part, be attributable to HLA selection.
- (3)
We identified two alleles, HLA-B*3501 and B*4403, that are associated with good control of viraemia
Conclusions
These data suggest that, within a given human population, HLA expression is an important determinant of viral sequence. Epitopes that are widely targeted may therefore be lost over time, due to accumulation of escape mutations.
Overall, these studies underline the importance of HLA as a potent evolutionary force in directing the future course of the HIV epidemic, and demonstrate that immune responses may operate differently according to the clade of infection. Therefore, we highlight the need