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.
