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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1003-1011
The Interleukin-12-Mediated Pathway of Immune Events Is
Dysfunctional in Human Immunodeficiency Virus-Infected Individuals
Jason D. Marshall,
Jihed Chehimi,
Giorgia Gri,
Jay R. Kostman,
Luis J. Montaner, and
Giorgio Trinchieri
From the Wistar Institute of Anatomy and Biology; the Division of
Immunologic and Infectious Diseases of the Children's Hospital of
Philadelphia; and the Philadelphia Field Initiating Group for HIV
Trials, Philadelphia, PA.
Interleukin-12 (IL-12) is a potentially critical factor in the
immune response against human immunodeficiency virus (HIV) because it
is important for regulating proliferation and interferon- (IFN-)
production by T cells and natural killer (NK) cells, antigen presentation and accessory cell function by macrophages and dendritic cells, and cytolytic activities of cytotoxic T-lymphocyte cells and NK
cells, which are all functions known to be dysfunctional in patients
with acquired immune deficiency syndrome. Peripheral blood mononuclear
cells (PBMC) from HIV-infected patients have been previously shown to
be deficient in the ability to produce IL-12 in response to the
bacterial pathogen Staphylococcus aureus Cowan. In this study,
impaired IL-12 production in cells from PBMC of HIV-infected patients
compared with healthy donors was observed across a broad panel of
stimuli derived from infectious pathogens with or without priming with
cytokines such as IFN- and IL-4, which amplify the IL-12 induction
signal. Analysis of p40 and p35 mRNA accumulation showed that
reductions in both subunits contribute to the lower IL-12 secretion of
cells from HIV-infected individuals. PBMC from HIV-infected donors also
failed to upregulate the IL-12 receptor  2 chain (IL-12R2) in
response to mitogenic stimuli. The expression of the IL-12R2 gene
could, however, be restored by in vitro exposure to rIL-12. Thus, it is
possible that a primary IL-12 defect may lead to secondary deficiencies in expression of the genes for IL-12R2 and IFN-, thus amplifying immune deficiency during HIV infection.
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