Institut de recherche biomédicale
     

    Mechanisms of HIV latency

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    Responsable du projet : Stéphane Emiliani

    Contact : stephane.emiliani@inserm.fr - Tel : +33 1 40 51 66 39

     

     

    The group

    Ahmed Abdouni (PhD student, ANRS)
    Meriem Hamoudi (Post-doc, ANRS)
    Emmanuel Ségéral (IE, Inserm)

     

    Objective

    The persistence of a latent reservoir containing replication-competent integrated provirus seriously challenges hopes for HIV eradication. We and others had previously identified LEDGF/p75 as a key factor of HIV integration that binds IN. LEDGF/p75 is a chromatin-associated protein interacting preferentially with post-transcriptionally modified histones that are associated with actively transcribed chromatin. LEDGF/p75 is responsible for the selective integration of HIV into active transcriptional units. Surprisingly, the same preference of HIV to integrate into active genes is also observed in latently infected cells harboring silenced proviruses. We are currently investigating the role of LEDGF/p75 in controlling post-integration transcription of HIV.

     

    Research interests

    We recently showed that LEDGF/p75 represses HIV expression in latently infected cells. We isolated a stable complex containing LEDGF/p75 associated with Spt6 and Iws1, two proteins involved the control of gene expression and chromatin structure. We showed that Iws1 plays a role in the establishment of latent infection. In latently infected cells, depletion of the complex results in reactivation of HIV promoter activity. Spt6 recruits Iws1 and LEDGF/p75 to the silenced provirus and maintains histone occupancy at the HIV promoter. Taken together, our results indicate that a complex containing LEDGF/p75, Iws1 and Spt6 participates in HIV latency.

    We are currently deciphering the molecular mechanisms by which LEDGF/p75 and Iws1 regulates gene expression. Furthermore, we are exploring the relationship between HIV integration site selection and the subsequent control of its transcription.

     

    References

    Gérard A, Ségéral E, Naughtin M, Abdouni A, Charmeteau B, Cheynier R, Rain JC, Emiliani S. The Integrase Cofactor LEDGF/p75 Associates with Iws1 and Spt6 for Postintegration Silencing of HIV-1 Gene Expression in Latently Infected Cells. Cell Host & Microbe. 2015 Jan 14;17(1):107-17.

     

    Financial Supports

    This program is supported by ANRS, SIDACTION and FP7.





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