A murine model for HIV/AIDS associated cryptococcal IRIS: characterizing the molecular mechanism of CD4+ T cell migration to the brain

Project Summary A hallmark of HIV-infection is the progressive depletion of CD4+ T cells, which renders HIV/AIDS patients more susceptible to infection with opportunistic pathogens such as the encapsulated fungus Cryptococcus neoformans. C. neoformans is a leading cause of mortality of HIV/AIDS patients and accounts for approximately 112,000 deaths worldwide annually. Antiretroviral therapy (ART) is a major advance in treating HIV/AIDS patients by restoring cellular immune responses including CD4+ T cell response. However, a rapid reconstitution and migration of CD4+ T cells to the brain in HIV/AIDS patients with cryptococcosis after initiation of ART frequently leads to immune reconstitution inflammatory syndrome (IRIS), an aberrant excessive immune response that is life-threatening with a mortality of 33% to 66%. Thus, CD4+ T cells play a central role in the aberrant lethal immune responses during HIV/AIDS associated cryptococcal IRIS. A critical gap in our understanding of cryptococcal IRIS remains: what is the molecular mechanism(s) of CD4+ T cell migration to the brain? TNF-α is a major biomarker of HIV/AIDS associated cryptococcal IRIS. However, how TNF-α contributes to cryptococcal IRIS is unknown. Based on our preliminary studies, we hypothesize that TNF-α signals directly on CD4+ T cells in a cell-intrinsic manner and drives CD4+ T cell migration to the brain through enhanced CD11a expression on CD4+ T cells during cryptococcal IRIS. Recently, a robust and physiologically relevant murine model of HIV/AIDS associated cryptococcal IRIS has been developed. This murine model of C. neoformans brain infection reproduces key aspects of cryptococcal IRIS of HIV/AIDS patients. Using this murine model, we will test our hypothesis by addressing the following aims: 1) To determine whether TNF-α signaling mediates CD4+ T cell migration to the brain in a cell-intrinsic manner during cryptococcal IRIS; and 2) To determine whether CD11a signaling is critically involved in CD4+ T cell migration to the brain in a cell-intrinsic manner during cryptococcal IRIS. If successful, the findings of this study would be fundamental for understanding HIV/AIDS associated cryptococcal IRIS and provide scientific basis for targeting TNF-α and CD11a signaling as a therapeutic strategy of cryptococcal IRIS.