| Popis: |
The CD8+ T (CTL) cell response is an important component of the immune response to HIV-1 infection. Presentation of peptides by the human leukocyte antigen (HLA) class I is key in directing that response. HLA-B*27:05 and HLA-B*57:01 have been consistently associated with immune control of HIV. To gain novel insights into the determinants of an effective CTL response mediated by these alleles, this work investigated cases of HIV disease control and progression in HLA-B*27:05 and B*57:01-expressing subjects. These subjects were either infected with clades of HIV infrequently found in combination with these alleles (C clade in HLA-B*27:05, and CRF01_AE clade in HLA-B*27:05/B*57:01) and/or represented the rare scenario of dual expression of both alleles. Transmission pair studies, viral replicative capacity assays and full-length ultra-deep sequencing were used to characterise CTL-mediated intra-host viral evolution, viral fitness and their effect on disease outcome. In the context of HLA-B*27:05 expression, this work demonstrated that the patterns of CTL immune escape and the associated viral fitness are considerably different in C clade compared to B clade HIV infection. This work also showed that rapid intra-host viral evolution and selection of escape may lead to disease progression despite expression of both favourable HLA class I alleles. The critical role of the Gag-specific CTL response in maintaining disease control, despite applying an unbiased genome-wide approach to detecting viral evolution, was demonstrated. This work has described the interactions between expression of HLA-B*27:05 and/or HLA-B*57:01, intra-host viral evolution and HIV disease progression, contributing to our understanding of CTL-mediated immune control. This is an important approach for elucidating correlates of protective immunity against HIV infection that may inform the design of intervention strategies. |
