Our research aims at elucidating the molecular mechanisms of HIV replication, in order to shed light on AIDS pathogenesis and to facilitate the development of novel antiviral therapies, and at exploiting HIV-derived lentiviral vectors for the genetic treatment of human diseases.

Over the years, our interest for HIV biology has gravitated around events that take place at the interface between the virus and its host cell. One target of our investigations has thus been the Nef early gene product of HIV, an importance virulence factor in vivo. In tissue culture, Nef induces the downregulation of CD4 and of MHC I, and alters signaling pathways. Our studies point to a general model in which Nef accomplishes these effects by acting as a connector between its targets and specific components of the cellular machinery. For instance, Nef bridges CD4 first with clathrin coated pits adaptor complexes and then with the b subunit of COP I coatomer, thereby triggering the rapid internalization and the lysosomal degradation of CD4. Nef-induced MHC I downmodulation stems from the same general principle, but in that case the downstream partner of Nef is a protein involved in endosome-to-Golgi trafficking. Emerging evidence suggests that such a connector model represents a paradigm for the regulation of a number of cell surface receptors.

A few years ago, our efforts to decipher the mechanisms allowing HIV infection of nondividing cells such as resting T lymphocytes and macrophages led us to develop a novel gene delivery system. Lentiviral vectors can govern the efficient in vivo delivery, integration and stable long-term expression of transgenes in a variety of non-mitotic tissues including neurons, hepatocytes, pancreatic b cells and hematopoietic stem cells. Our current goal is to explore the potential of lentivectors for the gene therapy of lympho-hematopoietic, hepatic and metabolic disorders.

Representative recent publications:

Cell, 97: 63, 1999; Curr. Biol., 9: 622, 1999; J. Virol., 72: 9873, 1998; EMBO J. 17: 2472, 1998; Proc. Natl. Acad. Sci. USA 94: 9825, 1997; Science 272: 263, 1996.