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    HIV: Quiescence and Proliferation


    Team leader : Florence MARGOTTIN


    Our team’s work focuses on the molecular conflicts which exist between viruses and their cellular hosts. These include the hijacking of the cellular machinery from the virus’ point of view, and overcoming the infection from the cell’s point of view.

    We are currently studying three viruses of major public health concern:

    - HIV-1 and HIV-2 which are both responsible for AIDS. Around 25 million people worldwide are infected with HIV-1 and an estimated 2.5 million new cases are reported each year. AIDS is responsible for 2 million deaths each year.  

     - Hepatitis B virus, HBV. Around a third of the world population (i.e. more than 2 million people) is infected with HBV, amongst which 350 million people are chronically infected. HBV chronic infection may lead to liver cancer.


    Our research focuses on the so-called viral “auxiliary” proteins. These proteins, which bear no structural or catalytic function, allow the virus to adapt to its host’s environment in order to ensure efficient replication and survival in the infected cells.




    Example of "molecular conflict" between the HIV-2 Vpx protein and a cellular restriction factor expressed in macrophages.


    An important contribution to HIV research is our demonstration that the Vpr and Vpx auxiliary proteins, whose mode of action was hitherto unknown, divert the host ubiquitination machinery. Both proteins, which are genetically related, recruit the DCAF1 protein, an adaptor of the Cul4 ubiquitin ligase. In light of our data, the long-known cytostatic activity of Vpr is now best explained by its use of DCAF1 to trigger the degradation of a still unknown cellular protein required for entry into mitosis. Unlike Vpr, Vpx is not cytostatic but is strictly required for macrophage infection by HIV-2. We have shown that Vpx recruitment of DCAF1 is critical for productive infection of human primary macrophages by HIV-2. Thus Vpr and Vpx divert the same ubiquitin ligase to presumably degrade distinct host factors, namely a constitutive factor of dividing cells in the case of Vpr and a macrophage-specific restriction factor in the case of Vpx.




    Model of action of Vpr. Vpr expressed by HIV-1 recruits the Cul4A-DDB1 ubiquitin ligase through DCAF1 interaction, leading to the ubiquitination and inactivation of a unknown target protein required for entry into mitosis.


    Our studies have also highlighted the complex interplay between the auxiliary Vpu and Vpr proteins and the host ubiquitination system. Both Vpr and Vpu are immune to the degradation process triggered by their usurped ubiquitin ligases and their own degradation involves other ubiquitin ligases. In the case of Vpu, a selective pressure appears to maintain its regulated degradation process at the expense of optimal viral egress from infected cells. In contrast, assembly of Vpr with the DCAF1 complex prevents its degradation, which preserves the activity of the incoming Vpr molecules during the early steps of the viral life cycle. 


    Our main lines of research are :

    - The search for host protein targets of the Vpr and Vpx proteins from HIV, and of HBx from HBV.

    - The search for the genuine function of HIV-1 Vpr.

    - The study of host factors from the innate antiviral defense arsenal, which represent potential targets of our viral proteins.

    We expect our studies to provide a better understanding of viral pathogenesis that might be taken into account in therapeutic strategies.