Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049057-06
Application #
6743650
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Sharma, Opendra K
Project Start
2000-09-15
Project End
2005-06-30
Budget Start
2004-06-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$299,000
Indirect Cost

  Institution

Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

DePaula-Silva, Ana Beatriz; Cassiday, Patrick A; Chumley, Jeffrey et al. (2015) Determinants for degradation of SAMHD1, Mus81 and induction of G2 arrest in HIV-1 Vpr and SIVagm Vpr. Virology 477:10-7
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
Planelles, Vicente; Barker, Edward (2010) Roles of Vpr and Vpx in modulating the virus-host cell relationship. Mol Aspects Med 31:398-406
Shah, Ankur H; Sowrirajan, Bharatwaj; Davis, Zachary B et al. (2010) Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu. Cell Host Microbe 8:397-409
Kauder, Steven E; Bosque, Alberto; Lindqvist, Annica et al. (2009) Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 5:e1000495
Bosque, Alberto; Planelles, Vicente (2009) Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 113:58-65
Planelles, Vicente; Benichou, Serge (2009) Vpr and its interactions with cellular proteins. Curr Top Microbiol Immunol 339:177-200
Rosenstiel, Paul E; Chan, Justin; Snyder, Alexander et al. (2009) HIV-1 Vpr activates the DNA damage response in renal tubule epithelial cells. AIDS 23:2054-6
Jacquot, Guillaume; Le Rouzic, Erwann; Maidou-Peindara, Priscilla et al. (2009) Characterization of the molecular determinants of primary HIV-1 Vpr proteins: impact of the Q65R and R77Q substitutions on Vpr functions. PLoS One 4:e7514
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

Showing the most recent 10 out of 19 publications