The PI has previously demonstrated that genetic alterations introduced into the human immunodeficiency virus type 1 (HIV-1) genome within specific transcription factor binding sites (C/EBP and Sp) in the long terminal repeat (LTR) are coordinately retained in proviruses at increasing frequencies during the course of HIV-1 disease and are preferentially encountered in LTRs derived from individuals with HIV-1 dementia (HIVD). A prototypical HIV-1 LTR genetic variant with this phenotype (3T/5T; containing a C-to-T change at position 3 of NF-KB-proximal C/EBP site I and a C-to-T change at position 5 of the promoter distal Sp site III) may conditionally facilitate immune evasion and viral replication in selected cell populations (cells of the monocyte/macrophage lineage) under specific physiologic/immunologic conditions that may involve relative levels of IL-6 or other cytokine/chemokine regulators that alter effector activity (including C/EBP and Sp factor levels). The hypothesis is that the """"""""3T/5T"""""""" LTR is representative of a conditionally operational LTR genotype that is preferentially retained in selected tissue compartments and because of specific functional properties is involved in disease pathogenesis in the peripheral blood and brain as HIV-1-associated disease increases in severity.
The specific aims are to (1) determine the effects of LTR backbone sequence, cell type, host cell differentiation/activation, and expression of HIV-1 regulatory proteins on the ability of the 3T/5T LTR to conditionally regulate viral gene expression within an integrated context; (2) identify NAprotein interactions involved in 3T/5T LTR regulation by C/EBP factors, Sp factors, and Vpr, and demonstrate the impact of 3T/5T LTR sequence on occupancy of relevant cis-acting binding sites; (3) analyze 3T/5T LTRs derived from brain of patients with or without minor cognitive motor disorder (MCMD) or dementia with respect to surrounding LTR sequence, activity in transient and stable expression analyses, and responsiveness to HIV-1 trans-activator proteins; and (4) determine the effects of LTR background sequence, cell type, host cell differentiation, and cellular activation on the ability of the 3T/5T LTR to conditionally regulate replication in HIV-1 infectious molecular clones. In lay language, the studies may lead to new ways to predict individuals more prone to developing brain disease and new ways to prevent, treat, and/or cure HIV-1-associated disease in the brain and perhaps other organ systems. ? ? ?
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