While HAART has reduced the incidence of HIV-related morbidity and mortality, increasing evidence suggests that chronic inflammatory medical illnesses, including cardiovascular disease, diabetes mellitus, chronic kidney and liver disease, osteoporosis, and cancer occur more frequently and/or at earlier ages in HIV infected individuals. Chronic HCV is similarly associated with liver inflammation and increased risk of diabetes mellitus, kidney disease, and cancer. HIV co-infection with HCV results in enhanced progression of inflammation-linked liver and kidney pathology relative to HCV infection alone. However, the pathogenesis of HIV-1 and HCV-related chronic inflammation is complex and incompletely understood. Inflammation in infection is orchestrated by innate immune cell signaling receptors that detect microbial molecules. A subset of intracellular immune receptors can assemble into multi-protein complexes called inflammasomes. Inflammasomes integrate two pathogen-triggered signaling cascades (signal 1 and 2), ultimately leading to secretion of the active, mature forms of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1?. Elevated serum IL-18 levels are associated with diabetes, with kidney disease and liver inflammation, and with increased atherosclerosis progression. We recently discovered that HIV and HCV virions assemble inflammasomes in monocytes and macrophages and that a subset of antibodies directed against envelope proteins from either virus can prevent monocyte IL-18 and IL-1? release in response to cognate virus. The mechanism through which antibodies specific for HIV or HCV prevent activation of the inflammasome by cognate virus and what antibody characteristics are critical for the process are unknown. Given the increased rates of inflammatory diseases in HIV infected people, our overall goal is to improve our understanding of mechanisms of inflammasome suppression to enhance control of HIV-associated inflammation.
In Aim 1, we will test whether co-infection increases inflammasome activation relative to monoinfection by comparing IL-18, IL-1?, and other proinflammatory cytokine levels in plasma from HIV infected, HCV infected, HIV/HCV co-infected, and uninfected subjects. Using a novel model system, we will assess the effect of HIV and HCV specific-antibodies on monocyte inflammasome activation with both viruses present.
In Aim 2, we will determine if envelope antibodies block one or both signals in the pathogen-triggered signaling cascades and correlate the degree of inflammasome inhibition to inhibition of the two signals.
In Aim 3, we will determine the role of the constant region (Fc) of anti-envelope antibodies in inflammasome inhibition. These studies will break new ground by revealing mechanisms of stimulation and modulation of inflammation triggered by chronic viruses, potentially explaining increased inflammation of the liver, kidney, and other organs and providing new therapeutic targets for modulation of that inflammation.
People with HIV infection develop heart disease, diabetes mellitus, chronic kidney and liver disease, osteoporosis, and cancer more frequently and/or at earlier ages than people without HIV. We will study how a pathway implicated in the development of these diseases is activated by viral infection. Determining the cause of this increased risk of heart and other disease in those with HIV infection and understanding how to reduce the risk is important.
