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    HIV: Retrovirus, Infection and Latency

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    Team leader : Florence Margottin-Goguet

     

    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.

     

    Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) are responsible for Acquired Immunodeficiency Syndrome (AIDS). Today, about 38 million people are living with HIV worldwide. HIV eradication faces a major obstacle that is viral persistence in reservoir cells despite treatment. HIV latency refers to silent viruses, which may remain competent for virus production if the treatment is interrupted. 

    HIV-1 and HIV-2 appeared in humans after cross-species transmission from non-human primate viruses (simian Immunodeficiency viruses or SIV). SIVcpz and SIVgor (infecting chimpanzee and gorilla, respectively) gave rise to HIV-1 on the one hand, SIVsmm (infecting sooty mangabey) to HIV-2 on the other hand. SIVsmm has also been transmitted to macaques (SIVmac). The different lineages share a similar “Gag-Pol-Env” organization but differ in their set of accessory proteins. For example, Vpx is found only in the HIV-2/SIVmac/SIVsmm and SIVrcm/mnd2 (infecting red-capped mangabey and mandrill) lineages. In contrast, all extant primate lentiviruses encode for Vpr, a paralog of Vpx, including SIVagm (infecting African green monkeys). These viral accessory 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.

    In some circumstances, cross-species transmission is blocked by host defence proteins, the so-called “restriction factors”. Restriction factors (RFs) provide a first line of defence against the virus within the host cell. They are characterized by their cell-autonomous antiviral activity and their interaction with a viral component. RFs often show signs of positive selection (an excess rate of non-synonymous mutations (dN) compared to the rate of synonymous mutations (dS)) that may be witnessed by comparing protein-coding sequences of genes from different host species. Those marks result from continual host-virus competition along evolution. This molecular arms-race can also be highlighted by the existence of viral antagonists in the form of the aforementioned viral accessory proteins. The mechanism of action of these viral antagonists often relies on the hijacking of a specific ubiquitin ligase to target the RF for degradation. 

     

    Objectives 

    The molecular battle at stake between the host cell and the virus is at the heart of the ongoing research of our team. Our general objectives are to better understand the role of viral auxiliary proteins and to identify and characterize host restrictions factors. 

    Our main lines of research are:

    -The search for host protein targets of the Vpr and Vpx proteins from HIV-1/HIV-2

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

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

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

     

    Selection of some contributions of the team to the HIV field

    -Discovery of the mechanism of action of HIV-1 Vpr (and first demonstration that HIV-2 Vpx uses the same ubiquitin ligase as Vpr)

    HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.

    Le Rouzic E, Belaïdouni N, Estrabaud E, Morel M, Rain JC, Transy C, Margottin-Goguet F.

    Cell Cycle. 2007 Jan 15;6(2):182-8.

     

    -Discovery of the mechanism of action of SAMHD1 in myeloid cells

    SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.

    Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F.

    Nat Immunol. 2012 Feb 12;13(3):223-228. 

     

    -Discovery of a new function of Vpx, its capacity to reactivate latent viruses through HUSH degradation

    HIV-2/SIV viral protein X counteracts HUSH repressor complex.

    Chougui G, Munir-Matloob S, Matkovic R, Martin MM, Morel M, Lahouassa H, Leduc M, Ramirez BC, Etienne L, Margottin-Goguet F.

    Nat Microbiol. 2018 Aug;3(8):891-897.

     

    Group composition

    MARGOTTIN-GOGUET Florence, team leader, Research director INSERM

    Orcid number: 0000-0002-3124-6690

    Researcher ID: F-9272-2013

    Web of Science: indicate for "author": "Margottin F or Margottin-Goguet F"

    Pubmed link :  http://www.ncbi.nlm.nih.gov/pubmed?term=Margottin-goguet F[Author] or Margottin F[Author]

     

     

    MOREL Marina, engineering assistant, CNRS

     

    MATKOVIC Roy, postdoc

     

    VAUTHIER Virginie, postdoc

     

    MARTIN Michael, PhD student

     

    LASSERRE Angélique, PhD student

     

    LARROUS Pauline, PhD student

     

    Selected publications

     

    HIV-2/SIV viral protein X counteracts HUSH repressor complex.

    Chougui G, Munir-Matloob S, Matkovic R, Martin MM, Morel M, Lahouassa H, Leduc M, Ramirez BC, Etienne L, Margottin-Goguet F. Nat Microbiol. 2018 Aug;3(8):891-897. 

    Specific Inhibition of HIV Infection by the Action of Spironolactone in T Cells.

    Lacombe B, Morel M, Margottin-Goguet F, Ramirez BC. J Virol. 2016 Nov 14;90(23):10972-10980. 

    HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages.

    Lahouassa H, Blondot ML, Chauveau L, Chougui G, Morel M, Leduc M, Guillonneau F, Ramirez BC, Schwartz O, Margottin-Goguet F. Proc Natl Acad Sci U S A. 2016 May 10;113(19):5311-6. 

    Evidence that HIV-1 restriction factor SAMHD1 facilitates differentiation of myeloid THP-1 cells.

    Dragin L, Munir-Matloob S, Froehlich J, Morel M, Sourisce A, Lahouassa H, Bailly K, Mangeney M, Ramirez BC, Margottin-Goguet F. Virol J. 2015 Nov 25;12:201. 

    HIV-1 Vpr induces the degradation of ZIP and sZIP, adaptors of the NuRD chromatin remodeling complex, by hijacking DCAF1/VprBP.

    Maudet C, Sourisce A, Dragin L, Lahouassa H, Rain JC, Bouaziz S, Ramirez BC, Margottin-Goguet F. PLoS One. 2013 Oct 8;8(10):e77320. 

    p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway. 

    Allouch A, David A, Amie SM, Lahouassa H, Chartier L, Margottin-Goguet F, Barré-Sinoussi F, Kim B, Sáez-Cirión A, Pancino G. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):E3997-4006. 

    Interferon block to HIV-1 transduction in macrophages despite SAMHD1 degradation and high deoxynucleoside triphosphates supply.

    Dragin L, Nguyen LA, Lahouassa H, Sourisce A, Kim B, Ramirez BC, Margottin-Goguet F. Retrovirology. 2013 Mar 11;10:30. 

    SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.

    Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F. Nat Immunol. 2012 Feb 12;13(3):223-228. 

    Molecular insight into how HIV-1 Vpr protein impairs cell growth through two genetically distinct pathways.

    Maudet C, Bertrand M, Le Rouzic E, Lahouassa H, Ayinde D, Nisole S, Goujon C, Cimarelli A,Margottin-Goguet F, Transy C. J Biol Chem. 2011 Jul 8;286(27):23742-52. 

    HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.

    Transy C, Margottin-Goguet F. Cell Cycle. 2009 Aug 15;8(16):2489-90.

    Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking.

    Mitchell RS, Katsura C, Skasko MA, Fitzpatrick K, Lau D, Ruiz A, Stephens EB, Margottin-Goguet F, Benarous R, Guatelli JC. PLoS Pathog. 2009 May;5(5):e1000450. 

     Human TRIM gene expression in response to interferons.

    Carthagena L, Bergamaschi A, Luna JM, David A, Uchil PD, Margottin-Goguet F, Mothes W, Hazan U, Transy C, Pancino G, Nisole S. PLoS One. 2009;4(3):e4894. 

    The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection.

    Bergamaschi A, Ayinde D, David A, Le Rouzic E, Morel M, Collin G, Descamps D, Damond F, Brun-Vezinet F, Nisole S, Margottin-Goguet F, Pancino G, Transy C. J Virol. 2009 May;83(10):4854-60. doi: 10.1128/JVI.00187-09. Epub 2009 Mar 4. 

    Assembly with the Cul4A-DDB1DCAF1 ubiquitin ligase protects HIV-1 Vpr from proteasomal degradation.

    Le Rouzic E, Morel M, Ayinde D, Belaïdouni N, Letienne J, Transy C, Margottin-Goguet F. J Biol Chem. 2008 Aug 1;283(31):21686-92. doi: 10.1074/jbc.M710298200. Epub 2008 Jun 4.

    Regulated degradation of the HIV-1 Vpu protein through a betaTrCP-independent pathway limits the release of viral particles.

    Estrabaud E, Le Rouzic E, Lopez-Vergès S, Morel M, Belaïdouni N, Benarous R, Transy C, Berlioz-Torrent C, Margottin-Goguet F.PLoS Pathog. 2007 Jul 27;3(7):e104.  

    HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.

    Le Rouzic E, Belaïdouni N, Estrabaud E, Morel M, Rain JC, Transy C, Margottin-Goguet F. Cell Cycle. 2007 Jan 15;6(2):182-8. 

     

    REVIEWS

    HUSH, a Link Between Intrinsic Immunity and HIV Latency.

    Chougui G, Margottin-Goguet F. Front Microbiol. 2019 Feb 12;10:224. 

    [Noise from Vpx: "HUSH"!]

    Chougui G, Martin M, Matkovic R, Etienne L, Margottin-Goguet F. Med Sci (Paris). 2019 Jan;35(1):9-12. 

    How SLX4 cuts through the mystery of HIV-1 Vpr-mediated cell cycle arrest.

    Blondot ML, Dragin L, Lahouassa H, Margottin-Goguet F. Retrovirology. 2014 Dec 11;11:117. doi: 10.1186/s12977-014-0117-5. Review.

    [SAMHD1 deprives HIV of nucleotides, essential for viral DNA synthesis].

    Lahouassa H, Dragin L, Transy C, Margottin-Goguet F. Med Sci (Paris). 2012 Nov;28(11):909-10. 

    Limelight on two HIV/SIV accessory proteins in macrophage infection: is Vpx overshadowing Vpr?

    Ayinde D, Maudet C, Transy C, Margottin-Goguet F. Retrovirology. 2010 Apr 9;7:35. Review.