HIV-specific cytotoxic CD8+ T cell responses play an important protective role against HIV infection. A number of studies, however, have indicated that HIV-specific CDS+ T cells may be functionally impaired. In addition, we recently have shown that HIV-specific CDS+ T cells exhibit increased susceptibility to undergo CD95/Fas-mediated apoptosis. This is of particular importance as HIV upregulates FasL on infected cells, while at the same time inhibits CD95/Fas-mediated apoptosis of infected cells. Indeed we have recently shown that HIV-infected macrophages can induce apoptosis of HIV-specific CDS+ T cells and this is largely due to CD95/Fas-mediated apoptosis. Furthermore HIV-specific CDS+ T cells lack the terminally differentiated CD45RA+CD62L- effector memory phenotype and this may affect the function of these cells in vivo. We recently have found evidence that CD95/Fas-mediated apoptosis may be responsible for this lack of differentiation. Thus HIV, by manipulating CD95/Fas-induced apoptosis, may be setting up an intricate CTL evasion and counterattack mechanism. Enhancing effector function, differentiation and/or survival of HIV-specific CDS+ T cells would enhance the efficiency of HIV-specific CD8+ T cells to control or clear HIV virus. Interleukin 15 (IL-15) is a pluripotent cytokine that expands in vivo memory CD8+ T cells, enhances their survival, and inhibits CD95/Fas-induced apoptosis. To date, no in depth investigation has been carried out on the effect of IL-15 on HIV-specific CD8+ T cells. We hypothesize that IL-15 treatment can enhance cytotoxic CDS+ T cells immunity against HIV This hypothesis is based on the known effects of lL-15 on mouse memory CDS+ T cells, and our own preliminary data that show that IL-15 can inhibit apoptosis and enhance effector function of HIV-specific CDS+ T cells. We propose to investigate the in vitro effect of IL-15 on effector function, differentiation, proliferation, and apoptosis of HIV-specific CDS+ T cells. We will also investigate the potential mechanism of action of IL-15 by examining the ASK1 signaling pathway and also examining gene expression using gene arrays. The studies in this proposal are novel and will provide valuable information on potential approaches to enhance the CD8+ T cell response against HIV in infected individuals. Information yielded from these studies will fill a knowledge gap as to the effect of IL-15 on anti-viral cytotoxic CDS+ T cell responses, and may prove useful for both novel therapeutic strategies and vaccine development for HIV infection and other viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052005-04
Application #
6886099
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Voulgaropoulou, Frosso
Project Start
2002-05-15
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$339,750
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Petrovas, Constantinos; Mueller, Yvonne M; Yang, Guibin et al. (2007) Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells. Apoptosis 12:2175-86
Petrovas, C; Mueller, Y M; Katsikis, P D (2005) Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy. Cell Death Differ 12 Suppl 1:859-70
Petrovas, Constantinos; Mueller, Yvonne M; Katsikis, Peter D (2004) HIV-specific CD8+ T cells: serial killers condemned to die? Curr HIV Res 2:153-62
Petrovas, Constantinos; Mueller, Yvonne M; Dimitriou, Ioannis D et al. (2004) HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. J Immunol 172:4444-53
Kim, Alfred H J; Dimitriou, Ioannis D; Holland, M Claire H et al. (2004) Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses. J Immunol 173:2524-9
Mueller, Yvonne M; Makar, Vera; Bojczuk, Paul M et al. (2003) IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector-memory T cells. Int Immunol 15:49-58
Mueller, Yvonne M; Bojczuk, Paul M; Halstead, E Scott et al. (2003) IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 101:1024-9
Maldonado, Anastacia; Mueller, Yvonne M; Thomas, Preethi et al. (2003) Decreased effector memory CD45RA+ CD62L- CD8+ T cells and increased central memory CD45RA- CD62L+ CD8+ T cells in peripheral blood of rheumatoid arthritis patients. Arthritis Res Ther 5:R91-6