The specific objectives of the proposed study include the identification of the anti-HIV factor produced by CD8+ cells. The investigator will use antibodies to known cytokines and, if necessary, a variety of protein analyses. The mechanism by which CD8+ cells suppress virus in a co-culture will also be investigated. Anti-cytokine antibodies will be used as well as antibodies to known cell surface and cell recognition molecules. These latter studies would evaluate whether direct cell contact and cell recognition are involved. Another objective of the applicant is to try to define the specific CD8+ cell subset(s) responsible for anti-viral activity. Using monoclonal antibodies to a variety of cell surface proteins, the applicant will attempt to assess, by flow cytometry, the phenotype of CD8+ clones with anti-viral activity as well as to study separated CD8+ cell sub-populations from HIV-infected individuals. If the cell subset is identified, the levels of this cell type could be easily monitored by fluorescent activated cell sorter (FACS) analysis. Another objective of the applicant is to try to determine whether the anti-viral activity is HIV-specific. The investigator proposes to assess if CD8+ cells from individuals with other viral infections show anti-HIV activity and if the anti-HIV CD8+ cells suppress replication of unrelated viruses such as herpes viruses or mouse retroviruses. If the activity is HIV-specific, the applicant will attempt to determine what viral proteins induce this response. Eventually, this information could be used to """"""""educate"""""""" CD8+ cells from non-responders or from potential donors of CD8+ cells, that is, for adoptive transfer. Finally, the investigator proposes to evaluate further whether the levels of anti-CD8+ cell activity vary in HIV-infected individuals at different clinical states and after immunization with viral proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030350-03
Application #
3145318
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1990-06-01
Project End
1993-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mackewicz, Carl E; Wang, Baikun; Metkar, Sunil et al. (2003) Lack of the CD8+ cell anti-HIV factor in CD8+ cell granules. Blood 102:180-3
Mackewicz, Carl E; Craik, Charles S; Levy, Jay A (2003) The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors. Proc Natl Acad Sci U S A 100:3433-8
Mackewicz, Carl E; Yuan, Jun; Tran, Patti et al. (2003) alpha-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS 17:F23-32
Levy, Jay A; Scott, Iain; Mackewicz, Carl (2003) Protection from HIV/AIDS: the importance of innate immunity. Clin Immunol 108:167-74
Levy, Jay A (2003) The search for the CD8+ cell anti-HIV factor (CAF). Trends Immunol 24:628-32
Mackewicz, C E; Lieberman, J; Froelich, C et al. (2000) HIV virions and HIV infection in vitro are unaffected by human granzymes A and B. AIDS Res Hum Retroviruses 16:367-72
Mackewicz, C E; Patterson, B K; Lee, S A et al. (2000) CD8(+) cell noncytotoxic anti-human immunodeficiency virus response inhibits expression of viral RNA but not reverse transcription or provirus integration. J Gen Virol 81:1261-4
Mackewicz, C E; Ridha, S; Levy, J A (2000) HIV virions and HIV replication are unaffected by granulysin. AIDS 14:328-30
Greco, G; Mackewicz, C; Levy, J A (1999) Sensitivity of human immunodeficiency virus infection to various alpha, beta and gamma chemokines. J Gen Virol 80 ( Pt 9):2369-73
Mackewicz, C E; Garovoy, M R; Levy, J A (1998) HLA compatibility requirements for CD8(+)-T-cell-mediated suppression of human immunodeficiency virus replication. J Virol 72:10165-70

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