. The long-term goal of this proposal is to gain a better understanding of the role of macrophages in the pathogenesis of AIDS. The rationale for this proposal is based on the evidence of widespread infection of tissue macrophages with HIV, high levels of monokines (IL-1, IL-6, TNFa, 7kDa T cell inhibitory monokine, TCIM) production in individuals with symptomatic HIV infection, and sustained production of certain monokines (IL-1a, IL-6, 7kDa TCIM) following in vitro HIV-1 infection of normal macrophages or macrophage tumor cells in investigator's model system. It is hypothesized that the sustained production of these monokines with immunoregulatory and inflammatory activities mediates the major disease manifestations of HIV infection.
The specific aims are: 1. To elucidate the mechanism of sustained IL-1a release by HIV-1 infected macrophages. Transcriptional regulation will be studied utilizing IL-1a gene promoter/reporter gene (CAT) constructs transfected into macrophages and T cells infected with HIV or co-transfected with HIV gene constructs. Post-transcriptional regulation and production and release of IL-1a will be studied in long-term macrophage cultures. 2. To obtain cDNA clones of the novel 7kDa T cell inhibitory monokine (TCIM) produced by HIV-1 infected macrophages for future studies on the regulation and pathogenic role of this monokine in AIDS, by screening with a neutralizing monoclonal antibody obtained in previous studies. 3. To define the viral requirements and role of monokines (IL-1a, Il-6, 7kDa TCIM) In a novel system of in vitro tumorigenesis dependent on HIV-1 infected macrophages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028196-05
Application #
2064291
Study Section
AIDS and Related Research Study Section 5 (ARRE)
Project Start
1989-03-01
Project End
1995-02-28
Budget Start
1993-03-01
Budget End
1995-02-28
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Berman, M A; Sandborg, C I; Wang, Z et al. (1996) Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus. J Immunol 157:4690-6
Sandborg, C I; Imfeld, K L; Zaldivar Jr, F et al. (1995) IL-4 expression in human T cells is selectively inhibited by IL-1 alpha and IL-1 beta. J Immunol 155:5206-12
Berman, M A; Zaldivar Jr, F; Imfeld, K L et al. (1994) HIV-1 infection of macrophages promotes long-term survival and sustained release of interleukins 1 alpha and 6. AIDS Res Hum Retroviruses 10:529-39
Sandborg, C I; Imfeld, K L; Zaldivar Jr, F et al. (1994) HIV type 1 induction of interleukin 1 and 6 production by human thymic cells. AIDS Res Hum Retroviruses 10:1221-9
Kawahara, D J; Everts, M; Buckingham, B et al. (1991) A naturally occurring 6-9-kilodalton interleukin-1 (IL-1) inhibitor prevents IL-1-mediated islet cytotoxicity but not IL-1-mediated suppression of insulin secretion. J Immunother (1991) 10:182-8
Sandborg, C I; Berman, M A; Imfeld, K L et al. (1990) Interleukin-1 and a 7-kDa T-cell inhibitory monokine reflect disease activity in infection with HIV-1. J Acquir Immune Defic Syndr 3:1148-54