Biomedical research institute
    You are here: Home / PhD program / Thesis defense / Molecular mechanism of HUSH complex antagonism by Vpx and Vpr lentiviral proteins

    Molecular mechanism of HUSH complex antagonism by Vpx and Vpr lentiviral proteins

    Michaël Martin

    Friday september 17 2021 at 2.30 pm

    Rosalind Franklin room, 2nd floor

    Institut Cochin, 22 rue méchain Paris 75014

    by videoconference

    Supervisor: Florence Margottin-Goguet

    Team: Retrovirus, Infection and Latency

    Department: Infection, Immunity, Inflammation



    HIV-1 and HIV-2, lentiviruses responsible of AIDS, appeared in human after cross-species transmissions from simian viruses (SIV). In addition to their structural and regulatory proteins, lentiviruses encode auxiliary proteins that promote viral replication in the host cell by counteracting antiviral cellular factors, called restriction factors. The mechanism of action of these viral auxiliary proteins often relies on the hijacking of Ubiquitin-Ligase complexes, a mechanism widely used by various pathogens, to degrade host cell proteins. This mechanism is used by the Vpx protein, expressed only by HIV-2 (and not by HIV-1), which induces the degradation of SAMDH1, a restriction factor blocking the reverse transcription step. Thus, Vpx molecularly bridges the DCAF1 adaptor of the Cul4A-DDB1DCAF1 Ubiquitin-Ligase complex with SAMHD1, resulting in ubiquitination and degradation of SAMHD1.

    In 2018, our team showed that Vpx induces the degradation of an additional cellular factor: the HUSH complex, composed of TASOR, MPP8 and Periphilin. This complex is involved in the epigenetic repression not only of many cellular genes, retro-transposable elements and endogenous retroviruses, but also of the HIV genome integrated into the infected cell. By degrading HUSH, Vpx promotes viral expression.

    In this context, the objectives of my thesis were to:

    (i) Determine whether HUSH degradation mechanism induced by HIV-2 Vpx was identical to SAMHD1 degradation mechanism. I was able to highlight important differences between the two mechanisms although Vpx uses, in both cases, the same Ubiquitin-Ligase adaptor, DCAF1 (main focus of the thesis work, submitted article).

    (ii) Characterize the molecular determinants involved in the antagonism of HUSH by other lentiviral proteins. First, we wanted to know if different Vpx-related viral proteins, in various simian virus species, had the same capacity to degrade the HUSH complex. This allowed us to reveal a lentiviral species-specificity of HUSH complex antagonism, a major characteristic of restriction factors (contribution to Chougui et al., Nature microbiology, 2018). Secondly, this led me to start studying the viral determinants of these Vpx-related proteins, such as the Vpr proteins from different strains of SIVagm (infecting the African green monkey) that present different phenotypes regarding both SAMHD1 or HUSH degradation (work in progress).

     All the results allowed us to better characterize the mechanism of HUSH antagonism by Vpx/Vpr lentiviral proteins, and to provide the first molecular tools to differentiate HUSH antagonism from SAMHD1 antagonism in primary cells. In the future, these data may help to better understand how various lentiviral proteins have adapted to their different cellular substrates (and vice versa) along evolution. Finally, targeting HUSH through the identification of interaction or degradation determinants could be interesting for the development of new therapeutic targets.