The long-term goal is to gain a better understanding of the pathogenesis of AIDS. It is not known how the human immunodeficiency virus type 1 (HIV-l) causes progressive immune deficiency and other features of ARC and AIDS such as fever, muscle wasting, and lymphadenopathy. The rationale for this proposal is based on the evidence of wide spread blood monocyte and tissue macrophage infection with HIV, increased monokine (IL-l, IL-6, TNFalpha, 6-9 kd inhibitor) production in HIV infected individuals. sustained production of these monokines by macrophage infected with HIV-l in vitro, and on the known activities of monokines (i.e. immune activation, suppression, fever, and muscle catabolism).
The specific aims are: 1. To prospectively study monokine production in blood monocytes from HIV seropositive asymptomatic individuals and to examine the correlation of individual monokine abnormalities (IL-alpha. IL- 1beta, IL-6, 6-9 kD inhibitor) with disease progression and certain disease manifestations (B cell lymphomas, opportunistic infections). 2. To characterize monokine secretion by macrophage infected with HIV in vitro and to study the possible requirement for cytokines as co-factors for the sustained monokine secretion and HIV replication. 3. In study the mechanism of HIV induced IL-1 and inhibitor transcription, mRNA stability, translation, and secretion by infected macrophage. If transcription of these factors is activated by HIV, IL-1 promoter fusions will be used to investigate activation by co-transfection with plasmids expressing HIV-1 tat, or by transfection into HIV-1-infected monocyte lines. 4. To further characterize the 6-9 kD inhibitor which is increased in AIDS and in HIV-1 infected macrophage cultures. The cloning of the cDNA (in progress) encoding this factor, and the recombinant protein will allow the study of the induction of this gene in HIV infection and its mechanism of immune.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028196-02
Application #
3142493
Study Section
Special Emphasis Panel (ARR (V2))
Project Start
1989-03-01
Project End
1992-02-29
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
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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