There is an urgent need to develop effective prophylactic and therapeutic vaccines to combat the human immunodeficiency virus (HIV)/AIDS pandemic, currently responsible for ~2 million deaths/year worldwide. The challenges encountered in developing vaccines to elicit broadly-neutralizing antibodies capable of blocking infection with diverse HIV strains, together with the wealth of evidence showing the importance of HIV-specific CD8 T cells in control of virus replication, have prompted efforts to develop T cell-inducing vaccines to combat HIV. However rational vaccine design is hampered by the current lack of understanding of features of an optimally-protective HIV-specific T cell response. HIV’s ability to evade T cell control by mutating to escape from T cell recognition suggests that it may be critical for vaccines to elicit broad T cell responses to limit viral escape. However T cell escape mutations can have fitness costs that may offset the effects of escape; furthermore transmission of unfit virus could lead to reduced viral replication in the recipient. We propose to perform an in-depth prospective analysis of viral interactions with the host CD8 T cell response in acute HIV infection to determine the importance of i. the fitness of the transmitted virus ii. the extent and kinetics of viral escape from the earliest CD8 T cell responses and iii. the viral fitness cost incurred in escaping from these early responses, in determining the prognostically-important set-point persisting viral load. This unique analysis of virus-host interplay will be made possible by the expertise in state-of-the-art molecular virological techniques that the fellowship applicant will bring to complement the host laboratory’s immunological expertise. Results from this study will give insight into whether vaccines should aim to induce CD8 T cell responses from which there is limited escape and/or induce responses that drive selection for escape mutations that reduce viral fitness.
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