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.
| Byrnes, Adriana A; Harris, David M; Atabani, Sowsan F et al. (2008) Immune activation and IL-12 production during acute/early HIV infection in the absence and presence of highly active, antiretroviral therapy. J Leukoc Biol 84:1447-53 |
| 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 |
