“Modulation of NKG2D and DNAM-1 activating receptors and their ligands during HIV-1 infection”.

Natural killer (NK) cells play a critical role in host defense against viral infections. Chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cell, that unsuccessfully control viral replication. However, the underlying mechanisms for this NK cell dysfunction are poorly understood. NK cells do not express an antigen specific receptor, as do other lymphocytes. Instead, NK cells encode a variety of different activating and inhibitory receptors and NK cell activation is dependent on a delicate balance between signals of opposite sign elicited by the multiple NK cell receptor–ligand interactions that follow NK cell–target cell interaction. The goal of my PhD project was to analyze the role of NK cell activating pathways upon HIV-1 infection. Specifically, I studied the modulation of the activating receptor NKG2D with particular interest on the mechanism of release, namely shedding, of its ligands (NKG2DLs) during HIV-1 infection in in vitro cell systems as well as in HIVinfected patients. Moreover, I investigated the modulation by viral proteins, such as Nef and Vpu, of PVR (Poliovirus Receptor, CD155, Necl-5) a ligand for another stimulatory receptor, DNAM-1 (DNAX accessory molecule-1 or CD226).The final goal of this work was to identify novel factors that regulate the function of immune responses against HIV-1 and that could provide new prognostic biomarkers and innovative antiviral strategies.