It remains controversial as to how CD4+ T cells directly infected with HIV die following infection. Numerous mechanisms have been proposed to account for infected cell killing, however none of the proposed mechanisms are universally accepted. It has long been recognized that one HIV protein, HIV protease, is intrinsically cytotoxic as its expression causes the death of bacteria, yeast, and mammalian cells, however it remains unclear how HIV protease kills these cells. Experimental data now demonstrate that HIV protease cleaves host cell proteins in addition to viral proteins. Our laboratory has recently defined one mechanism by which HIV protease can kill cells; specifically HIV protease can cleave the apoptosis initiating protein, procaspase 8, to result in its activation. Thereafter, a traditional apoptosis cascade is initiated, ultimately resulting in the structural, nuclear, and morphologic changes associated with apoptosis. While we have demonstrated that this mechanism of HIV protease mediated killing can occur, we have yet to determine whether or not this mechanism does occur, particularly in vivo. The focus of the current proposal is to define the relevance of this form of cell killing both in infections, which occur in the test tube, as well as in patients. The clinical significance of this research may be reflected in recent clinical observations, suggesting an altered diseased course of patients who have infections with HIV that contain mutations within the HIV protease gene as compared to those that do not. We will explore the potential impact of these mutations by assessing the differential impact of wild type HIV protease versus mutant protease on procaspase 8 activation and cell killing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062261-05
Application #
7395050
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$308,700
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Trushin, Sergey A; Carena, Alberto A; Bren, Gary D et al. (2012) SDF-1? degrades whereas glycoprotein 120 upregulates Bcl-2 interacting mediator of death extralong isoform: implications for the development of T cell memory. J Immunol 189:1835-42
Schnepple, David J; Shepard, Brett; Bren, Gary D et al. (2011) Isolation of a TRAIL antagonist from the serum of HIV-infected patients. J Biol Chem 286:35742-54
Rizza, Stacey A; Challagundla, Kishore B; Natesampillai, Sekar et al. (2011) TRAIL dependent fratricidal killing of gp120 primed hepatocytes by HCV core expressing hepatocytes. PLoS One 6:e27171
Cummins, N W; Badley, A D (2010) Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis 1:e99
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
Rizza, Stacey A; Cummins, Nathan W; Rider, David N et al. (2010) Polymorphism in tumor necrosis factor-related apoptosis-inducing ligand receptor 1 is associated with poor viral response to interferon-based hepatitis C virus therapy in HIV/hepatitis C virus-coinfected individuals. AIDS 24:2639-44
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
Cummins, Nathan; Badley, Andrew (2009) The TRAIL to viral pathogenesis: the good, the bad and the ugly. Curr Mol Med 9:495-505
Bren, Gary D; Trushin, Sergey A; Whitman, Joe et al. (2009) HIV gp120 induces, NF-kappaB dependent, HIV replication that requires procaspase 8. PLoS One 4:e4875

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