The proposed research concerns a population of end-stage memory CD8 T cells that accumulates during HIV disease progression. CD8 T cells with similar characteristics are generated as the final stage of cell cultures subjected to repeated rounds of antigen-driven proliferation. Cultures that have reached this terminal state of """"""""replicative senescence"""""""" are characterized by irreversible cell cycle arrest, apoptosis resistance, shortened telomeres, altered cytokine profiles, reduced anti-viral functions, and permanent loss of CD28 gene expression. Clinical studies have shown that high proportions of CD8 T cells that lack CD28 expression are correlated with reduced antibody response to influenza vaccination and with increased mortality risk in the elderly, as well as with a variety of suppressor cell functions, suggesting that the high proportions of CD8+CD28 - in persons infected with HIV may affect disease progression. The ability to explore these interactions in cell culture model systems provides an unparalleled opportunity to experimentally dissect the genetic and molecular basis of several fundamental aspects of HIV pathogenesis and to evaluate potential immunomodulatory strategies. The following Specific Aims will be addressed: (1) To evaluate the effects of senescence on CD8 T cell function and correlate these findings to HIV-1 infection. Long-term cultures and clones will be used to follow function, cytokine production, and associated phenotypic characteristics during the entire trajectory to senescence. CD8 T cells with similar phenotypes isolated from HIV-infected persons will be tested ex vivo for the corresponding functions and cytokine changes; (2) To explore the indirect effects of CD8 T cell senescence on other immune functions. Cells and cell-free supernatants from senescent versus early passage CD8 T cell cultures will be compared for effects on autologous CD4 T cell function, CD8 effector activity, B cell antibody production and antigen-presentation by dendritic cells. Interactions identified for CD8 T cells that have been """"""""aged"""""""" in vitro will be validated using cells with the same phenotype isolated from HIV-infected persons; (3). To determine if strategies that prevent replicative senescence in CD8 T cells also prevent some of the deleterious immune effects identified in Aims 1 and 2. Gene transduction (hTERT, CD28) as well as estrogen effects on the process of replicative senescence will be used to determine the optimal means for maintaining the functional profile of HIV-specific CD8 T cells with respect to both direct and indirect immune effects. This novel approach to analysis of the immune exhaustion in HIV disease may yield promising strategies for immunotherapy to retard or prevent progression to AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060362-04
Application #
7212267
Study Section
Special Emphasis Panel (ZRG1-AARR-E (01))
Program Officer
Finzi, Diana
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$366,235
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Chou, Jennifer P; Effros, Rita B (2013) T cell replicative senescence in human aging. Curr Pharm Des 19:1680-98
Dock, Jeffrey N; Effros, Rita B (2011) Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence. Aging Dis 2:382-397
Effros, Rita B (2011) Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. Exp Gerontol 46:135-40
Parish, Stanley T; Kim, Sarah; Sekhon, Rekha K et al. (2010) Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes. J Immunol 184:2847-54
Parish, Stanley T; Wu, Jennifer E; Effros, Rita B (2010) Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes. J Clin Immunol 30:798-805
Parish, Stanley T; Wu, Jennifer E; Effros, Rita B (2009) Modulation of T lymphocyte replicative senescence via TNF-{alpha} inhibition: role of caspase-3. J Immunol 182:4237-43
Chen, Wilbur H; Kozlovsky, Bernard F; Effros, Rita B et al. (2009) Vaccination in the elderly: an immunological perspective. Trends Immunol 30:351-9
Effros, Rita B (2009) Kleemeier Award Lecture 2008--the canary in the coal mine: telomeres and human healthspan. J Gerontol A Biol Sci Med Sci 64:511-5
Fauce, Steven Russell; Jamieson, Beth D; Chin, Allison C et al. (2008) Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol 181:7400-6
Choi, Jenny; Fauce, Steven R; Effros, Rita B (2008) Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun 22:600-5

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