Despite rapid advances made in our understanding of the Molecular Biology and host range of HIV-1, some of the intrinsic details by which the HIV-1 induces AIDS remain a mystery. In efforts of advancing our knowledge in regards to the AIDS Phenomena, changes in the expression functionality of protein factors involved in the control of growth and proliferation of human T-lymphocytes in HIV-1 positive individuals, require a closer examination. Recently, the possible involvement of Molecular Chaperones, a specialized class of phylogenetically conserved proteins, in cell proliferation, growth and transformation, in addition to providing protection from thermal and other stresses, has attracted considerable interest. For instance, there are indications that several Molecular Chaperones (e.g hsp 70 and hsp 90) may have functional roles in stress responses and growth of human T lymphocytes. Thus, it has been postulated that both proteins are preferentially synthesized in the mid G1 phase, the portion of the cell cycle responsible for the variability in cell duration and growth rate and, account for a significant proportion of synthesis in nitrogen-activated cells. Indeed, activation of T cells constitutes a very important area of study within retrovirology and AIDS. Proviral activation is closely linked with T cell activation and we need to gain a better understanding of this process as a requirement to manipulate the system to the benefit of AIDS patients. Since Molecular Chaperones play important roles in numerous cellular physiological processes, it is reasonable to speculate that the expression and function of these proteins may be altered during HIV infection as compared to normal individuals. The long term goal of the present application is to unravel the mechanics of Molecular Chaperones during mitogen-induced human T cell activation and to determine if changes in that scenario are induced after HIV infection. The long term goal will be approached through the following specific aims: (1) To study the kinetics of gene expression for Molecular Chaperones, at the transcriptional and translational levels, during mitogen induced T cell activation, (2) To establish correlations between the kinetics of gene expression for Molecular Chaperones and other protein factors, required for T cell activation, such as cytokines and protooncogenes, (3) To identify the Molecular Chaperones that are constitutively expressed and those which are induced or suppressed at different stages of T cell activation, and to partially characterize them, (4) To evaluate the degree of protein phosphorylation on Molecular Chaperones during T cell activation, (5) To determine the site of phosphorylation in Molecular Chaperones during T cell activation and, (6) To study the ultracellular location of Molecular Chaperones in T cells at different stages during activation by Immunoelectron Microscopy.
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