The understanding of systemic as well organ-specific disease in AIDS is hampered by an incomplete understanding of basic issues in HIV immunopathogenesis. For example, the specific mechanisms underlying the profound suppression of cell-mediated immunity associated with HIV infection remain unclear. Interleukin-12 (IL-12), which is produced primarily by monocyte/macrophages, is critical for the generation of cell- mediated immune responses. Mononuclear cells from HIV patients are markedly impaired in their ability to produce Il-12. The in vitro treatment of such cells with Il-12 ameliorates deficient T and NK cell responses, suggesting that this defect in Il-12 production plays a pathogenetic role in the suppression of CMI due to HIV infection. The in vitro infection of primary monocytes with HIV replicates this suppression of Il-12 production, providing evidence that a direct interaction between HIV and monocytes may be responsible for deficient Il-12 responses in AIDS. We recently defined a novel pathway of IL-12 regulation: the cross-linking of a cell-surface regulator of complement activation (CD46) by either antibody or complement activation products directly and specifically inhibits monocyte production of Il-12. Notably, HIV virions and productively infected cells are coated with complement activation products which are ligands for CD46. Such complement opsonization has been shown to mediate non-CD4-dependent HIV uptake by monocytic and other cells expressing complement receptors and regulatory proteins. Our data suggests that such complement opsonization may be directly responsible for the defective Il-12 production seen in HIV infection. In these studies we aim to define the role of complement in the suppression of monocyte production of Il-12 production induced by infection with HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012167-03
Application #
2749377
Study Section
Special Emphasis Panel (ZDE1-YS (31))
Project Start
1996-09-30
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Karp, C L; Wills-Karp, M (2001) Complement and IL-12: yin and yang. Microbes Infect 3:109-19
Wysocka, M; Robertson, S; Riemann, H et al. (2001) IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness. J Immunol 166:7504-13
Karp, C L; Grupe, A; Schadt, E et al. (2000) Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1:221-6
Karp, C L; Wysocka, M; Ma, X et al. (1998) Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance. Eur J Immunol 28:3128-36