HIV-1 infection of the central nervous system induces a variety of clinical abnormalities including dementia, ataxia, and memory loss. Progressive multifocal leukoencephalopathy (PML) represents one of the most common neurological complications of HIV-1 infection. PML is a fatal demyelinating disease that results from the reactivation of the human neurotropic polyomavirus, JCV, and its infection of oligodendrocytes and astrocytes. Once a rare disorder, the higher incidence of PML among AIDS patients suggests cross-communication between HIV-1 and JCV in the brain. Results from molecular biology and virology studies have established the ability of Tat to augment the JCV genome. This event requires, at least in part, a cellular protein named Pur-alpha, a single stranded DNA and RNA binding protein whose expression is controlled during brain development. Pur-alpha also stimulates HIV-1 gene expression and its association with Tat augments Tat activation of the LTR. Furthermore, Pur-alpha controls JCV DNA replication and gene expression in glial cells by interacting with the JCV early protein, T-antigen. Pur-alpha has an unusual structural feature allowing the protein to interact with various important cellular proteins in addition to nucleic acids. Ablation of Pur-alpha in animal models causes incomplete brain development. Our preliminary observations have shown the ability of Pur-alpha to control cell cycle progression and prolong cells with damaged DNA in S-phase. On the other hand, Pur-alpha has shown the ability to interact with Rad51 (a key factor in the homologous recombination pathway), decrease the level of Rad51 gene transcription, and interfere with the function of Ku70, one of the major components of the non-homologous end-joining pathway. These observations ascribed a new role for Pur-alpha as a gatekeeper of DNA repair, which ensures the efficient and appropriate repair of DNA with high levels of fidelity and accuracy by modulating cell cycle progression and the level of expression and activity of factors involved in cellular DNA repair machinery. Support for this observation stems from our results showing substantial chromosomal abnormalities associated with dysfunctional repair in cells lacking Pur-alpha. In light of these observations one can envision a model in which the physical interaction of Pur-alpha with the JCV regulatory protein, T-antigen, and the HIV-1 transactivator protein, Tat, will have a functional consequence on the ability of Pur-alpha to execute its role in DNA repair during the course of HIV-1 infection and JCV reactivation. In this project, experiments are proposed to delineate the effect of Pur-alpha on DNA repair mechanisms seen in astrocytes and oligodendrocytes, and determine the impact of JCV and HIV-1 upon Pur-alpha functions in cell cycle regulation and genomic stability. The outcome of these studies will provide important information which can be utilized to better understand the indirect communication of two distinct viruses by cellular proteins and their cooperative role in the progression of diseases in the CNS.
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