Jones, Nicola Ann; (2002) Investigation of the early HIV-1-specific CD8+ T cell response and the selection of escape viral variants. Doctoral thesis (Ph.D.), University College London.

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Abstract

HIV-1 causes a persistent infection in humans ultimately associated with the development of AIDS. Events in early HIV-1 infection play a critical role in determining the subsequent disease course: the persisting viral load established at this time is predictive of the rate of progression to AIDS. The virus-specific CD8+ T cell response is temporally associated with the decline in primary viraemia, and is thought to play an important role in control of virus replication. Why this response fails to mediate more complete control of early virus replication is not clear. Here, the early HIV-specific CD8+ T cell response was characterised in patients who naturally contained early viral replication with differing efficiencies. In patients who established a high persisting viral load, the functional virus-specific CD8+ T cell response detected in primary infection was frequently weak, limited in breadth and only increased in magnitude after the acute burst of viral replication was contained. In a typical patient studied in depth, responses to different viral epitopes expanded in a hierarchy of immunodominance; but in another patient, a more rapid expansion of T cells of a single epitope specificity was seen in acute infection. In these patients there was rapid evolution of the in vivo viral quasispecies to sequentially escape from the initially immunodominant and subdominant T cell responses. By contrast, in a patient who established a low setpoint viral load there was more rapid expansion of a strong, broad virus-specific T cell response during acute HIV infection, associated with the emergence of mutations in only a limited number of T cell epitopes in tat. Rapid development of a broad virus-specific CD8+ T cell response and a lack of evolution of escape viral variants are thus associated with the establishment of a low setpoint viral load and efficient long-term control of virus replication.

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