CFAR Awards

Michael Chattergoon, MD, PhD

Infectious Diseases, Johns Hopkins School of Medicine

Recognition of HIV by the inflammasome signaling complex

Michael Chattergoon, MD, PhD - Image

Inflammation-associated diseases occur more frequently in HIV infected individuals.  However, the pathogenesis of HIV-related inflammation and inflammation-associated disease progression is poorly understood.  Prolonged inflammasome activity has been associated with disease progression in several chronic inflammatory diseases.  We previously demonstrated elevated levels of IL-18, an inflammasome cytokine/product, in individuals with uncontrolled HIV as well as elite suppressors.  We also established that monocyte uptake of HIV results in IL-18 production through activation of the NLRP3 inflammasome.  This process is independent of the HIV Env-CD4 and CCR5 interaction, but can be blocked by endocytosis inhibitors.  In this proposal, we aim to further define the mechanism by which monocytes recognize and respond to HIV, by developing methods to further characterize the inflammasome activation signals.  In Aim 1, we will examine the role of Toll-like Receptors (TLR) in signaling the inflammasome during HIV infection.  In Aim 2, we will study further steps of the endocytic process including endosome acidification, endosome maturation and endosome-lysosome function, to deteremine whether HIV-1 induced inflammasome activation is dependent on these processes.