The long-term career goal of this candidate is to establish an independent, extramurally-funded research program in Kenya focused on issues pertaining to global HIV-1 infection, integrating the fields of immunology, virology and epidemiology. The career development plan of this award allows the candidate the opportunity and funding to gain experience in the areas of epidemiology and virology at the University of Washington and in cutting-edge immunology at Oxford University and to advance as an independent academician. Further virological training applied to population-based epidemiological approaches will increase the candidate's ability to conduct more scientifically integrated research at the University of Nairobi, will facilitate transfer of knowledge to researchers here, and ultimately enhance the quality of research conducted on site. HIV-1 infection in newborn children is a global health crisis of unprecedented proportions, with the preponderance of the burden falling on sub-Saharan Africa. The natural history of HIV- 1 infection in children infected early in life is much more severe than in adults infected for a similar duration. The mechanisms behind the accelerated disease course remain uncertain, but evidence indicates the quality of the CD8+ cytotoxic T lymphocyte (CTL) immune response elicited during acute infection may be important. This proposal aims at defining the quality of the CTL responses in HIV-1 infected infants and the role of CTL escape variants in HIV-1 disease progression. Preliminary studies have shown that HIV-1 infected infants as young as one month of age are capable of mounting a CTL response against HIV-1, that the prevalence of the response increases with the age of the infant. Futher detailed studies on longitudinal blood samples from a large cohort are planned to investigate the quantity and quality of the CTL response in HIV-1 infected infants in association with disease progression. Parameters investigated will include the durability of the response and changes in epitope recognition patterns over time. Additionally, the role of CTL escape HIV-1 variants will be investigated in a subset of HIV-1 infected mother-infant pairs to determine if viral varients capable of evading the infant's immune response contribute to disease progression in the infant. ? The resulting findings will directly apply to the development of vaccine strategies for prevention of mother to child transmission of HIV-1. ? ?
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