| dc.description.abstract | Sub-Saharan Africa remains the global epicenter of the HIV epidemic; more than 70% (25 million) of all people living with HIV/AIDS are in Africa. To end the global epidemic, finding an effective HIV vaccine remains a top priority. A small fraction of people including children infected with HIV do not progress to disease (AIDS) for 10 or more years without antiretroviral therapy – the long-term non-progressors (LTNPs). HLA class I molecules are critical in the elimination of HIV infected cells through presentation of endogenously processed antigens to CD8+ cytotoxic T lymphocytes (CTL). Understanding what and how these genetic factors control viremia provides opportunities for development of new HIV vaccines and immunotherapies.
In this thesis, we first focused on estimating how many children in Uganda and Botswana infected with HIV are classified as LTNPs and the factors associated with progression. We found that one in every 16 children infected with HIV is a LTNP. Additionally, being underweight at baseline, having been enrolled after 2010 into care and being from Botswana were associated with faster progression to disease. We demonstrate that these associations remain the same when we include a baseline HIV viral load measurement in the model.
Next, we examined the HLA class I alleles associated with LTNP among children from Botswana and Uganda. We found that certain HLA class I alleles are over-represented in HIV infected children compared to the uninfected populations. In addition to the canonical alleles HLA-B*57:03 and B*58:01, we documented a novel HLA-C*03:02 allele that was associated with LTNP, and that its protective effect is additive and independent of linkage disequilibrium. Together these alleles account for 16.5% of the variation in LTNP status.
Finally, we focused on elucidating the mechanisms through which HLA-C*03:02 controls HIV infection. We documented that HLA-C*03:02 prefers to present peptides derived from structural HIV proteins, and more specifically a Gag GY9 peptide located in the p17 matrix protein. Positions E62, T142 and E151 in the HLA-C*03:02 peptide binding groove and positions p6 in GY9 are crucial in shaping the immune response and supposedly account for HIV immune escape pathways. Lastly, we demonstrated that the GY9 peptide elicits a clade-specific HLA-C*03:02-mediated response in one third of individuals carrying the allele.
In conclusion, these results support a role for HLA-C molecules in HIV control and provide prospects for development of new vaccine and immunotherapies targeting CTL responses. | en_US |
