Grant: Operating Grant: Innovative Biomedical and Clinical HIV/AIDS Research

Autophagy is an intracellular bulk degradation process characterized by the formation of a structure named the autophagosome that delivers intracellular material to lysosomes for degradation. In recent years, the role of autophagy in antiviral immunity has been increasingly studied. Exposure to HIV-1 increases autophagy in human cells, which may upregulate or downregulate specific processes associated with innate immunity (such as the production of interferons) or with acquired immunity (such as antigen presentation). TRIM5alpha is a cytoplasmic, interferon-stimulated, anti-retroviral protein that can directly bind and inhibit incoming retroviruses. In addition to this effector function, TRIM5alpha is a sensor able to activate innate immune pathways associated with an antiviral state. TRIM5alpha and other TRIM proteins were recently found to stimulate autophagy, but whether autophagy contributes to the TRIM5alpha sensor functions is completely unknown. In this project, we will investigate the respective roles of autophagy and TRIM5alpha in the induction of innate immune pathways in human lymphocytes and monocytes exposed to HIV-1. We will use various genetic and pharmacological tools to turn off or, conversely, to upregulate autophagy in order to determine its importance in the establishment of a TRIM5alpha-dependent antiviral state in these cells. This project will allow us to uncover the importance of autophagy and TRIM5alpha in the innate immune response against HIV-1 and may reveal novel pharmacological targets.