OTK18 Regulation in HIV-1 associated dementia

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The transcriptional factor, OTK18, has recently been shown by our group to regulate HIV-1 infection in mononuclear phagocytes (MP). Interestingly, OTK18 is specifically expressed in the cytosol of brain MP in severe HIV-1 encephalitis but not in other neurodegenerative disorders and may thus serve as a "surrogate" marker for the development of HIV-associated dementia (HAD). To further develop these observations we will determine why OTK18 can be expressed at relatively high levels in advanced disease and yet fail to control viral growth in brain target cells. Our preliminary data indicates that the E-twenty six-1 binding sequence (EBS) of the HIV-1 long termminal repeat is a critical element for OTK18 suppression. EBS is also located in the proximal region of the OTK18 promoter, suggesting an autoinhibitory mechanism of gene expression. In this application, we hypothesize that EBS binding along with OTK18 endoproteolysis regulate OTK18 activity in HAD. Furthermore, we will address the discrepency between high OTK18 levels in disease. and its anti-retroviral functions. We believe this apparent contradiction to be due to endoproteolytic cleavage of OTK18 in infected macrophages leading to its cytoplasmic localization and viral escape from OTK18 suppression. In that context, viral escape from OTK18 suppression will correlate with HAD. To examine these hypotheses, the following questions will be asked:1) What is the mechanism(s) for HIV-1 induction of OTK18 expression?, 2) What is the mechanism of viral from OTK18 suppression in HAD?, and 3) What is the mechanism of OTK18 endoproteolysis? We posit that molecular characterization of OTK18 will lead to a better understanding of the dual complex roles of MP viral regulation and its role in the neuropathogensis of HIV-1 infection. We will address the following specific aims;1) To study the role of promoter elements in OTK-18 function. 2) To study the mechanism of viral escape from OTK18 suppression in HAD, and 3) To characterize OTK18 processing and function. The proposed research is innovative, as viral regulation by a zinc finer protein and escape from OTK18 suppression by EBS mutation is a new paradigm. Our findings may also have an important impact in the field of zinc finger molecules, since OTK18 is located on chromosome 19q13, where clusters of retroviral integration sites and zinc fingers are evolutionally co-localized.
StatusFinished
Effective start/end date1/1/0512/31/10

Funding

  • NATIONAL INSTITUTE OF MENTAL HEALTH: $251,205.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $257,250.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $243,920.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $243,920.00
  • NATIONAL INSTITUTE OF MENTAL HEALTH: $243,920.00

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