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Thesis Research Summary:
Human immunodeficiency virus type 1 (HIV-1)-associated immunologic and neurologic disease is dependent on the ability of the virus to infect resident immune and central nervous system (CNS) cell populations. In vitro and in vivo investigations have shown that HIV-1 infection of CD4+ T lymphocytes initiates a highly productive infection in stimulated T cell populations. In contrast, HIV-1-infected monocytic cell populations produce only limited quantities of virus within the context of a more chronic infection. The chronic nature of HIV-1 replication in cells of monocyte/macrophage lineage is a likely contributor to the central importance of these cells in evasion of HIV-1 detection by the immune system and the maintenance of viral reservoirs. Moreover, cells of this lineage can be used by the virus as a vehicle which facilitates its transport through the blood-brain barrier and its entry to the CNS, therefore promoting the development of HIV-1-associated neuropathogenesis and HIV-1 dementia (HIVD). HIV-1 viral gene expression in monocytes and macrophages (as well as T cells and other cell types susceptible to infection) is critically dependent on regulation of the long terminal repeat (LTR), the promoter element that drives expression from proviral DNA and guides the synthesis of potentially toxic viral proteins and infectious virus.
Factors that influence the level of LTR-directed transcription include sequence variation within cis-acting regulatory elements, alteration of the levels and specific activities of cellular transcription factors during the course of cellular differentiation and activation, and the complex network of signaling pathways that converge on the LTR. The LTR, in turn, relies heavily on participation of viral factors, such as Tat and Vpr, as well as cellular transcription factors, including NF-κB, ATF/CREB, and members of the CCAAT/enhancer binding protein (C/EBP) and Sp family of proteins. C/EBP and Sp regulation of HIV-1 viral gene expression in cells of the monocytic and macrophage lineage is modulated by sequence variation that occurs naturally within the C/EBP and Sp sites and throughout the proviral genome.
Recent studies demonstrated that specific HIV-1 LTR C/EBP configurations that arise as a consequence of quasispecies evolution were preferentially encountered in the brain and exhibited enhanced LTR-directed transcriptional activity. More studies have demonstrated the accumulation of a 3T C/EBP site I and 5T Sp site III as peripheral disease severity increased. These studies also showed that these two sequence variants were co-selected and that the 3T C/EBP site I variant correlated with HIVD. My thesis research currently is focused on better understanding the significance of these sequence variants with respect to LTR activity and viral replication. |