Suppression of HIV-1 in CNS by a novel protein from St. John's Wort.+ The transcription process is the first step in the reactivation of HIV-1 genome that eventually leads to complete cytolytic destruction of host cells. As such, since the discovery of HIV-1 there has been a major effort to understand the mechanism by which the viral genome is transcribed and to identify the therapeutic strategies to intervene in this process. In the central nervous system (CNS), microglia, macrophages, and astrocytes are the primary cells that harbor HIV-1 and support, albeit to various degrees, expression and replication of the HIV-1 genome. Earlier studies have ascribed important roles for several transcription factors such as the C/EBPa family, NFkB (p50/p65), and the viral transactivator, Tat, and the late auxiliary protein, Vpr, in these cells. Further, it was evident that cross-interplay of these factors with each other and their specific partners are the key determinants of their activities. Of particular interest was the notion that some of the pathways that are involved in the activation of the HIV-1 genome by Tat also engaged in dysregulated expression of host factors that are implicated in the neuropathogenesis of AIDS. Thus, targeting of these specific viral and cellular activators may provide an effective tool for blocking direct and indirect pathways that are involved in AIDS/CNS injury. In this research proposal we build on our preliminary data indicating that a novel protein, p27SJ, derived from a callus culture of Hypericum perforatum (also known as St. John's Wort) has the ability to physically and functionally interact with Tat and C/EBPa, and impairs their activities upon the HIV-1 genome in microglia and astrocytes. We propose to launch a comprehensive study to 1) unravel the molecular basis of p27SJ suppression of HIV-1 by assessing the interplay of C/EBPa and Tat, and their impact on the overall contribution of various transcription factors that are implicated in LTR transcription. The outcome of this molecularly based project will provide important information and biological tools which, in turn, can be utilized in the future to devise therapeutic tools for halting viral gene expression and replication, and blocking Tat-induced stimulation of pro-inflammatory factors which are implicated in the pathogenesis of AIDS associated neurological problems

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH074392-01A2
Application #
7167359
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Kopnisky, Kathy Lynn
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$320,625
Indirect Cost
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Sachdeva, Rakhee; Darbinian, Nune; Khalili, Kamel et al. (2013) DING proteins from phylogenetically different species share high degrees of sequence and structure homology and block transcription of HIV-1 LTR promoter. PLoS One 8:e69623
Bookland, Markus J; Darbinian, Nune; Weaver, Michael et al. (2012) Growth inhibition of malignant glioblastoma by DING protein. J Neurooncol 107:247-56
Darbinian, Nune; Gomberg, Rebeccah; Mullen, Loriann et al. (2011) Suppression of HIV-1 transcriptional elongation by a DING phosphatase. J Cell Biochem 112:225-32
Amini, Shohreh; Merabova, Nana; Khalili, Kamel et al. (2009) p38SJ, a novel DINGG protein protects neuronal cells from alcohol induced injury and death. J Cell Physiol 221:499-504
Darbinian, Nune; Czernik, Marta; Darbinyan, Armine et al. (2009) Evidence for phosphatase activity of p27SJ and its impact on the cell cycle. J Cell Biochem 107:400-7
Darbinian, Nune; Popov, Yuri; Khalili, Kamel et al. (2008) Creation of a bi-directional protein transduction system for suppression of HIV-1 expression by p27SJ. Antiviral Res 79:136-41