Abstract

Progression of Human Immunodeficiency Virus (HIV) disease to Acquired Immunodeficiency Disease Syndrome (AIDS) involves the loss of CD4+ T cells that provide critical helper activity for humoral and cell-mediated immune responses. Although multiple mechanisms have been proposed to account for the depletion of T cells, the effects of gp120 on cell survival are likely multiple, and involve not only immune cells, but other parenchymal tissues as well. Experiments proposed in this application seek to address the molecular basis and functional consequences of gp120-stimulated CXCR4 signaling. The present application will test the hypotheses: that gp120 ligation of CXCR4 in activated cells initiates PKCa, Lck, p38, and Bim-dependant signal cascade resulting in loss of mitochondria! transmembrane potential with consequent caspase activation and apoptosis (Specific Aim #1); that caspase cleavage intermediates directly transactivate NF-KB-mediated HIV-LTR transcription (Specific Aim #2); and that these events drive CD4 depletion and HIV replication in vivo (Specific Aim #3). ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI040384-09A2
Application #
7229142
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
1998-04-01
Project End
2011-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
9
Fiscal Year
2007
Total Cost
$370,000
Indirect Cost

  Institution

Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905

  Publications

Cummins, Nathan W; Sainski, Amy M; Natesampillai, Sekar et al. (2014) Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cells. Mol Cell Ther 2:1
Cummins, Nathan W; Neuhaus, Jacqueline; Sainski, Amy M et al. (2014) Short communication: CD4 T cell declines occurring during suppressive antiretroviral therapy reflect continued production of Casp8p41. AIDS Res Hum Retroviruses 30:476-9
Badley, A D; Sainski, A; Wightman, F et al. (2013) Altering cell death pathways as an approach to cure HIV infection. Cell Death Dis 4:e718
Cummins, Nathan W; Weaver, Eric A; May, Shannon M et al. (2012) Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice. FASEB J 26:2911-8
Cummins, Nathan W; Klicpera, Anna; Sainski, Amy M et al. (2011) Human immunodeficiency virus envelope protein Gp120 induces proliferation but not apoptosis in osteoblasts at physiologic concentrations. PLoS One 6:e24876
Sainski, Amy M; Natesampillai, Sekar; Cummins, Nathan W et al. (2011) The HIV-1-specific protein Casp8p41 induces death of infected cells through Bax/Bak. J Virol 85:7965-75
Taylor, Julie A; Cummins, Nathan W; Bren, Gary D et al. (2010) Casp8p41 expression in primary T cells induces a proinflammatory response. AIDS 24:1251-8
Cummins, Nathan W; Rizza, Stacey A; Badley, Andrew D (2010) How much gp120 is there? J Infect Dis 201:1273-4; author reply 1274-5
Natesampillai, Sekar; Nie, Zilin; Cummins, Nathan W et al. (2010) Patients with discordant responses to antiretroviral therapy have impaired killing of HIV-infected T cells. PLoS Pathog 6:e1001213
Cummins, Nathan W; Jiang, Wei; McGinty, John et al. (2010) Intracellular Casp8p41 content is inversely associated with CD4 T cell count. J Infect Dis 202:386-91

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