14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 47)

Clarisse Berlioz-Torrent
Inst Cochin, Paris, France

BACKGROUND: Retroviruses envelope glycoproteins (Env) play an essential role in the viral replicative cycle. They are responsible for the virus entry into the host cell and are the main target of cellular and humoral immune responses. We and others have previously demonstrated that trafficking and cell surface expression of HIV-1 Env glycoproteins are governed by interactions between several trafficking signals located in the cytoplasmic domain of Env and clathrin-associated adaptor complexes AP-1 and AP-2. Furthermore, our data also highlighted the importance of the binding of the HIV-1 Env to TIP47, a protein initially involved in intracellular trafficking of MPR. We showed that the Env-TIP47 interaction mediates the retrograde transport of Env from endosomes to the TGN. We also demonstrated that mutations in Env cytoplasmic domain, impairing the binding of TIP47, blocked Env incorporation into HIV virions.

RESULTS: The presence of Env in HIV-1 virions is essential for infectivity, but to date, the molecular mechanisms by which Env is packaged into HIV-1 virions is largely unknown. Our recent studies indicate that TIP47 is the first cellular cofactor essential for Env incorporation into HIV-1 virions, allowing the encounter and physical association between HIV-1 Gag and Env proteins during the viral assembly process. Indeed, we demonstrated that silencing of TIP47 by siRNA impairs Env incorporation, virion infectivity, and abolished co-immunoprecipitation of Gag with Env. By contrast, overexpression of TIP47 increased Env packaging into HIV-1 particles. Furthermore, we reported an interaction between TIP47 and the MA domain of Gag. Mutations blocking MA-TIP47 interaction inhibited Env incorporation, virion infectivity and colocalization between Gag and Env products. Finally, we demonstrated that TIP47 binds both the cytoplasmic domain of Env and MA domain simultaneously, serving as a bridge between Env and Gag proteins without the contribution of other cellular partners.

CONCLUSIONS: In conclusion, we have identified TIP47 as a cellular co-factor involved in the incorporation of full-length HIV-1 Env into HIV-1 Gag particles. This function involves the interaction between TIP47 and 2 essential viral proteins, Gag and Env, making TIP47 indispensable for HIV-1 Env incorporation and HIV-1 infectivity.

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2007-02-25
47

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