IL-18 is a proinflammatory cytokine that is elevated in HIV-1 infection (7, 8) and is thought to contribute to HIV/AIDS pathogenesis by inducing Th2 cytokine production (12, 13). IL-18 and IL-1beta are structurally related cytokines that require caspase-1 cleavage for processing and release (3, 5). Intracellular bacterial activation of a multi-protein complex known as the inflammasome has been implicated in caspase-1 activation and IL-beta processing and release (21). We hypothesized that HIV-1 infection of monocyte derived macrophages (MDMs) can induce inflammasome activation, leading to IL-18/IL-1beta processing and release.
Aim #1 will address this hypothesis by a series ELISA, Western Blots, immunoprecipitation and immunodepletion experiments.
Aim #2 will address the mechanism by which HIV-1 may induce inflammasome activation. We postulated that HIV-1 may activate the inflammasome by inducing inflammasome gene expression or by having a direct interaction with an inflammasome component. We will test both of these mechanisms by a series of Real Time PCR, gene delivery, siRNA, immunoprecipitation, Western Blot and immunodepletion experiments. Taken together, the results from these experiments will provide a better understanding of the mechanisms by which HIV-1 infection induces high levels of IL-18 secretion and may lead to new avenues for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI061828-03
Application #
7153495
Study Section
Special Emphasis Panel (ZRG1-ONC-O (29))
Program Officer
Hernandez, Milton J
Project Start
2004-12-01
Project End
2007-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$30,445
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Raices, Raquel M; Kannan, Yashaswini; Bellamkonda-Athmaram, Vedavathi et al. (2009) A novel role for IkappaBzeta in the regulation of IFNgamma production. PLoS One 4:e6776