It has recently been reported that the rate at which T-cells in HIV-1 infected individuals are replaced may reach 1 billion per day. The mechanisms by which T-cells are killed are therefore of paramount importance, since a slight advantage in the ratio of living to dying T-cells might significantly alter the course of the disease. Cell death may be caused directly by the virus infecting the cell or indirectly by the results of virus infecting other cells. A major form of cell death in T-cells is Fas- mediated apoptosis, and evidence suggests that apoptosis in AIDS patients is at least in part Fas-mediated. We have developed a model of HIV-induced cell death in which expression of the viral envelope protein, gp160 in cultured lymphocytes, greatly enhances Fas-mediated apoptosis. This enhancement is apparently calmodulin dependent, since it correlates with calmodulin expression and can be interdicted by calmodulin inhibitors. Our goal is to identify the mechanisms by which gp160 enhances Fas-mediated apoptosis. To that end our specific aims are: Determination of the Ca2+ calmodulin signal transduction pathways utilized in gp160 enhanced Fas-mediated apoptosis. Determination of the points in Fas signaling pathways which are necessary for gp160 enhancement of Fas-mediated apoptosis; and identification of the molecular determinants of gp160 that are responsible for enhanced Fas- mediated apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072823-03
Application #
2712834
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Finerty, John F
Project Start
1996-06-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
2000-05-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Micoli, Keith J; Mamaeva, Olga; Piller, Sabine C et al. (2006) Point mutations in the C-terminus of HIV-1 gp160 reduce apoptosis and calmodulin binding without affecting viral replication. Virology 344:468-79
Ahn, Eun-Young; Pan, George; Vickers, Selwyn M et al. (2002) IFN-gammaupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma. Int J Cancer 100:445-51
Radding, W; Williams, J P; McKenna, M A et al. (2000) Calmodulin and HIV type 1: interactions with Gag and Gag products. AIDS Res Hum Retroviruses 16:1519-25
Micoli, K J; Pan, G; Wu, Y et al. (2000) Requirement of calmodulin binding by HIV-1 gp160 for enhanced FAS-mediated apoptosis. J Biol Chem 275:1233-40
Pan, G; Vickers, S M; Pickens, A et al. (1999) Apoptosis and tumorigenesis in human cholangiocarcinoma cells. Involvement of Fas/APO-1 (CD95) and calmodulin. Am J Pathol 155:193-203
Pan, G; Zhou, T; Radding, W et al. (1998) Calmodulin antagonists inhibit apoptosis of CD4+ T-cells from patients with AIDS. Immunopharmacology 40:91-103