Abstract

The mechanisms leading to CD4 T cell depletion in HIV-infected individuals remain to be determined. Certain viral infections including HIV infection lead to a chronic activation state of the immune system that results in an enhanced state of susceptibility to apoptosis in a variety of immune cells. In addition, HIV infection specifically triggers an enhanced level of susceptibility to Fas-dependent apoptosis in peripheral CD4 T cells. A second HIV specific sequelae is the induction of FasL expression in antigen presenting cells such as macrophages. Based on the preferential and specific interaction between CD4 T cells and macrophages, this proposal will address the hypothesis that encounter of the Fas susceptible CD4 T cell with a FasL expressing macrophage leads to selective depletion of the CD4 T cells. Preliminary data demonstrate that both mechanisms, increased susceptibility to Fas in CD4 T cells, and increased FasL expression in macrophages, is observed not only in in vitro models but in HIV-infected patients. Understanding the molecular mechanisms regulating susceptibility of primary CD4 T cells to Fas-dependent apoptosis (Aim I), and identifying the regulation of FasL expression in macrophages by HIV-dependent mechanisms (Aim II) will be used to test relevance in HIV-infected patients (Aim III). Results from these three aims should establish the clinical relevance of the HIV induced dysregulation of Fas/FasL interactions as a cause of CD4 T cell depletion in HIV-infected patients.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040384-03
Application #
6169900
Study Section
Special Emphasis Panel (ZRG5-ARRA (04))
Program Officer
Plaeger, Susan F
Project Start
1998-04-01
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$241,425
Indirect Cost

  Institution

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

  Publications

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
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
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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