| Popis: |
Infection with HIV is a continuing global health problem. Antiretroviral therapy effectively suppresses viraemia, but the viral reservoir in latently infected CD4+ T-cells persists for decades and is the main obstacle to HIV eradication. The central role of CD8+ T-cellmediated immune control of natural adult HIV infection has long been established and recent studies suggest that CD8+ T-cells are likely to be crucial in eliminating reactivated reservoirs. However, the questions of what constitutes an effective anti-HIV CD8+ T-cell response and how to induce it therapeutically are outstanding. Moreover, even less is known about the antiviral function of CD8+ T-cells in paediatric HIV infection. Although outnumbered by adult infections, paediatric infection may offer opportunities to achieve HIV cure that could be more widely applicable to cure strategies in adults. Here, I explore the specific aspects of the interplay between host and virus in order to gain a better understanding of the optimal CD8+ T-cell-mediated immune responses. I demonstrate that in contrast to the Gag-specific response that mediates viral control in the context of HLA-B*57, among HLA-B*14-restricted responses, Env-specific cells are more potent than those targeting Gag. This is associated with higher antigen sensitivity and stronger selection pressure in the Env-specific population. I define two broadly distinct phenotypes of HIV non-progression in children. These are characterised by differential protein specificity of the antiviral CD8+ T-cell response but children of both phenotypes demonstrate strong selection pressure exerted on the virus by CD8+ T-cells in the first weeks of life. Next, in the context of the HIV vaccine tested in the Phambili trial, I report an HLA-specific effect of vaccine on disease progression, as a result of altering the natural CD8+ T-cell immunodominance hierarchy. Finally, I demonstrate a new method which allows to selectively deplete human HIV-specific CD8+ T-cell in vitro, and thereby to evaluate the contribution and efficacy of particular CD8+ T-cell specificities to viral inhibition - a critical question to HIV vaccine design and reservoir eradication studies. The work described here adds important insights to our understanding of the HIV-specific CD8+ T-cell responses that are generated from birth through childhood and into adulthood and is relevant to the future studies directed at harnessing the most effective CD8+ T-cell response to achieve HIV cure. |
