The extent of CNS dysfunction observed during HIV-l infection is likely due to both host and viral factors that include but are not limited to differences in receptor and coreceptor expression, physiology of target cell populations, cytokine and chemokine expression, neurotoxicity of viral proteins such as gpl2O Tat, and Nef, functional properties of the long terminal repeat (LTR), and functional properties of the viral trans-activator proteins, Tat and Vpr. The studies proposed in this competitive renewal application will continue to examine the structural evolution of the HIV-1 LTR and its interaction with several families of cellular transcription factors and viral trans-activators (Tat and Vpr) within cells of the monocyte/macrophage lineage. Of particular importance will be studies focused on examining the relationships of these biomolecular interactions with progressive HIV-1-associated neurologic dysfunction. The GENERAL HYPOTHESIS to be tested is that the C/EBP transcription factor family, in concert with other cellular factors and the HIV-1 protein Vpr, interact with specific configurations of C/EBP sites I and II to activate viral gene expression in cells of the monocyte/macrophage lineage. Based on clinical observations, in vivo animal model studies, and in vitro tissue culture investigations performed by a number of Investigators, increased genomic expression can potentially lead to an increased CNS viral load and/or an enhanced production of viral neurotoxic proteins gp120, Tat, and/or Nef, leading to glial and/or neuronal dysfunction and CNS disease progression. We propose that evolution of the HIV-1 LTR as well as the Vpr and Tat genes within cells of the monocyte/macrophage lineage prior to or after entry into the CNS plays a critical role in the overall outcome of this process. renewal application are to examine the: (1) physical and functional interaction of the C/EBP transcription factor family with the HIV-1 LTR and other cellular factors critical to viral genome activation; (2) interaction of C/EBP factors and HIV-l Vpr with C/EBP binding sites I and II within the HIV-l LTR and the impact of sequence variation and other cellular transcription factors on these interactions; (3) interaction of HIV-1 Vpr with the viral LTR within the context of HIV-1 infectious molecular clones and primary cell populations derived from peripheral blood and CNS; (4) functional correlations between high affinity interactions of HIV-1 Vpr with specific configurations of C/EBP binding site I and HIVD; and (5) structural co-evolution of the HIV-1 LTR and Vpr gene during HIV-l CNS infection, in o propagation in cells of the monocyte/macrophage lineage, and functional correlations between LTR/Vpr co-evolution and HIVD. These studies may provide insight relevant to the development of new molecular diagnostic reagents and therapeutic strategies to monitor and control HIV-1-associated neurologic disease.
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