Wong, M.; (2006) Characterisation of the virus-specific CD8+ T cell response in acute and early HIV-1 infection. Doctoral thesis , University of London.

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Abstract

The primary human immunodeficiency virus type 1 (HIV-1) - specific CD8+ T cell response plays an important role in control of early viral replication. The nature of this response may thus be among the factors determining the prognostically-important persisting viral load. Here, the primary HIV-specific CD8+ T cell response was characterised in a small cohort of patients, to gain insight into quantitative and qualitative features of the response and their relationship to the efficiency of control of virus replication. The majority of patients studied established intermediate or high persisting viral loads. In these individuals, no association was found between the persisting viral load established and the total magnitude of the early HIV- specific CD8+ T cell response, its epitope breadth or specificity. However the response was observed to be heavily biased towards the most immunodominant epitopes. Kinetic analyses of epitope-specific responses revealed that in most patients, responses expanded asynchronously, with rapidly-expanded responses being immunodominant in primary infection. Mechanisms that may account for the rapid initial expansion of selected responses in acute viral infection, including high avidity and pre-existence of cross-reactive memory cells, were explored using murine models. Notably, the most rapidly-expanded epitope-specific response(s) typically did not reach peak magnitude until several weeks after the peak in acute viral replication and the fastest response was observed in the one patient studied who established a low persisting viral load. Phenotypic studies suggested that HIV-specific CD8+ T cells exhibit an "immature" phenotype from primary infection onwards in all patients. Although these studies need to be extended to a larger number of patients, the results obtained suggest that the kinetics and synchronicity of expansion of epitope-specific CD8+ T cell responses in primary HIV-1 infection may be among the factors that impact on the efficiency of control of primary viraemia.

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