Control of HIV-1 gene transcription at different stages during the course of infection requires a delicate balance of interaction among various host factors and viral proteins. In the central nervous system (CNS), cells of neural origin such as astrocytes and peripheral cells of macrophage/monocytic lineage are the primary sites for the expression of the HIV-1 genome. However, the mechanism which modulates expression of the viral genome during the infection cycle in CNS cells, i.e. the immediate early stage when basal transcription of the viral genome is initiated by host factors; at the early stage when host factors cooperate with the viral transactivator, Tat; and at the late stage when other viral regulatory proteins such as Vpr participate in viral gene transcription, remains unknown. HIV-1 infection of CNS cells is accompanied by induction/dysregulation of several critical pathways required for the maintenance of host function. One of the viral proteins that has an established role in affecting host function is Tat, which has the ability to communicate with several regulatory factors to augment transcription of the HIV-1 LTR and alters the level of expression from the host genome. Our recent results demonstrate upregulation of Rad51, a cellular gene which is implicated in homologous recombination, in brain cells of patients with HIV-1 encephalopathy (HIVE). Further, in vitro studies revealed the ability of Tat to elevate Rad51 expression in astrocytes and neuronal culture. As the elevation in Rad51 may affect, directly or indirectly, HIV-1 gene expression and replication, we examined transcription of the viral promoter in the presence of an elevated level of Rad51 and demonstrated the ability of Rad51 to increase basal-and Tat-induced expression of the HIV-1 genome. Preliminary observations from our deletion mutants revealed the importance of the LTR sequence spanning -120 to -80 in Rad51 activation of the LTR in human astrocytes suggesting the involvement of a series of transcription factors such as C/EBP family and NF-kappaB, whose activities are mediated, at least in part, through their interaction with the DNA sequence. Thus, we hypothesize that cross-communication of Rad51 with transcription activators such as C/EBPbeta and NF-kappaB families and Tat results in a positive feedback regulatory event that leads to stimulation of the HIV-1 gene expression in CNS cells. To test our hypothesis we will employ a comprehensive approach using state of the art techniques of molecular biology to decipher the cooperative interaction of Rad51 with various cellular proteins such as C/EBPbeta, CHOP, NF-kappaB, and p53, and viral proteins such as Tat and Vpr and assess their impact on the HIV-1 genome at the immediate early, early, and late phases of viral gene expression. The outcome of these studies will provide important information which can be utilized in the current treatment of AIDS patients and in devising more effective molecular strategies toward inhibition of viral gene expression in the CNS.
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