The VPR gene from HIV-1 encodes a 96 amino acid protein that induces apoptosis in infected lymphocytes. VPR induces apoptosis independently of the presence and function of p53, and in a manner that is mediated by activation of the cystine-aspartate proteases 3 and 8. The objective of the present study is to understand at a molecular level the mechanisms by which HIV-1 VPR induces apoptosis. Studies will first examine the possibility that VPR activates apoptosis pathways that normally function in response to death receptor activation or DNA damage. Studies will next be conducted to examine the degree of activation or inactivation of survival pathw0ays that normally prevent entry into apoptosis. Macrophages will then be examined to determine the impact of long-term, chronic infection by HIV-1 and the relationship to apoptosis. And lastly, studies will examine patterns of gene expression in an attempt to identify undefined cellular genes whose transcription is modified during VPR induced apoptosis.
Specific aims of this proposal are:
aim 1. To define the apoptosis signaling cascade that is activated by VPR.
Aim 2. To examine the role of the survival pathway in VPR induced apoptosis.
Aim 3. To examine the effect of VPR on the viability of primary macrophages.
Aim 4. To identify differentially expressed cellular genes during VPR induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049057-04
Application #
6534314
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Sharma, Opendra K
Project Start
2000-09-15
Project End
2005-05-31
Budget Start
2002-09-01
Budget End
2003-05-31
Support Year
4
Fiscal Year
2002
Total Cost
$255,000
Indirect Cost
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Cassiday, Patrick A; DePaula-Silva, Ana Beatriz; Chumley, Jeffrey et al. (2015) Understanding the molecular manipulation of DCAF1 by the lentiviral accessory proteins Vpr and Vpx. Virology 476:19-25
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Ward, Jeffrey; Davis, Zachary; DeHart, Jason et al. (2009) HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog 5:e1000613

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