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Defining the role of T cell metabolism in HIV-induced chronic immune activation and immune dysfunction.

A. K. M. Nur-Ur Rahman

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Canadian Institutes of Health Research (CIHR)
The molecular and cellular pathways that lead from HIV infection to AIDS are complex, multifactorial and not understood. However, a number of recent studies have identified several key immune features in HIV infected individuals that characterize the progression to AIDS. One such feature is the state of general chronic immune activation in HIV individuals, which is a better predictor of AIDS progression than viral load. We have yet to understand the underlying causes and maintenance of chronic immune activation that is often exasperated by immune dysfunction in HIV individuals. The depletion of CD4+ T cells and the expansion of non-functional CD8+ T cells confound the search for underlying factors. Since chronic immune activation is a key player in the pathogenesis of AIDS, therapeutic interventions to reduce it may positively impact the overall immune function in HIV individuals. Altered metabolism in T cells in HIV individuals could be an underlying factor of chronic immune activation. Mammalian target of rapamycin (mTOR), a protein molecule, is a key regulator of metabolism that once activated directs T cell activation, differentiation and function. mTOR controls not only the positive signals to direct functions of T cells but also the negative signals to turn itself off when not required. Dysregulated mTOR has been implicated in cancer where normal growth is sacrificed for uncontrolled growth to the detriment of the organism and likewise loss of mTOR retards growth. The hypothesis of my project is that in HIV infection T cells fail to either turn off or tone down mTOR activities leading to chronic immune activation and immune dysfunction. To date, mTOR functions with metabolism have not been investigated in T cells from HIV. The goal of my project is to define the interplay between mTOR, metabolism and chronic immune activation, and with this knowledge therapeutic interventions could be developed to reduce chronic immune activation and immune dysfunction.

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