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2014

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Cellular restriction in HIV-1: study of translational complexes of APOBEC3G/3F antiviral factors during HIV-1 infection

Research unit

UPR 9002 - Architecture et réactivité de l'ARN (IBMC)
15, rue Rene Descartes 67084 - Strasbourg Cedex

Group

Name: Retrovirus et Virus à ARN

Group leader: PAILLART-MARQUET Jean-christophe/roland - jc.paillart@ibmc-cnrs.unistra.fr

Group leader's phone: 33388417035

Website: Visit website

Group organization:
- Chercheurs: 5
- ITA: 1
- Doctorants: 3
- Post-Docs: 2
- Autres: 1

Publications of the team linked to the topic (3 last years):
1) Batisse, J., Guerrero, S.X., Bernacchi, S., Richert, L., Godet, J., Goldschmidt, V., Mely, Y., Marquet, R., de Rocquigny, H. & Paillart, J.-C. (2013) APOBEC3G impairs the multimerization of the HIV-1 Vif protein in living cells. J. Virol. 87, 6492-6506
2) Batisse, J., Guerrero, S.X., Bernacchi, S., Sleiman, D., Gabus, C., Darlix, J.-L., Marquet, R., Tisné, C. & Paillart, J.-C. (2012) The role of Vif oligomerization and RNA chaperone activity in HIV-1 replication. Virus Res., 169, 361-376
3) Bernacchi, S., Mercenne, G., Tournaire, C., Marquet, R. & Paillart, J.-C. (2011) Importance of the proline-rich multimerization domain on the oligomerization and nucleic acid binding properties of HIV-1 Vif. Nucleic Acids Res., 39, 2404-2415.

About PhD

PhD Director: PAILLART Jean-christophe - jc.paillart@ibmc-cnrs.unistra.fr

Phone: 33388417035

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Cellular restriction in HIV-1: study of translational complexes of APOBEC3G/3F antiviral factors during HIV-1 infection

Project: The genome of HIV-1 encodes several “auxiliary” proteins that are not usually found in other retroviruses but are essential for infection and development of pathogenesis in vivo. Among them, the viral infectivity factor (Vif) is essential for virus replication in non-permissive cells (CD4+ T lymphocytes, monocytes, macrophages), the main reservoir for HIV-1 in vivo. In these cells, Vif counteracts the activity of the antiviral factors APOBEC3G (Apolipoprotein B mRNA-Editing Enzyme Catalytic polypeptide 3G or 3G) and A3F by inducing their degradation through the proteasome and by inhibiting their translation, thus, indirectly, decreasing their incorporation into viral particles.
The goal of this thesis project is twofold. In a first part, the PhD candidate will decipher the mechanisms by which Vif inhibits A3G/3F translation. Is there a direct effect of Vif on the initiation complex of translation or a cellular redistribution of A3G mRNA in the presence of Vif? We have shown that Vif specifically interacts with the untranslated regions (UTRs) of A3G mRNA, and that this interaction is probably responsible for the translational inhibition. First, based on the literature, the candidate will study 5'UTR mutants of A3G/3F mRNAs to validate hypotheses concerning the mode of translational initiation of these mRNAs. Second, by using wild-type and mutant Vif proteins, the candidate will define the domains required for this inhibition. At the cellular level, he/she will study the location, in presence or absence of Vif, of A3G/3F mRNAs (wild-type or mutated in their 5'UTR) by FISH. He/she will test specifically their presence in cytoplasmic microdomains involved in the storage and metabolism of mRNAs (P-Bodies, stress granules, granules of Staufen) by confocal microscopy.
In a second part, the PhD candidate will determine the role of HDAC6 (histone deacetylase 6) in the formation of a new A3G degradation complex. It has been shown that this protein would regulate the entry of HIV-1 into host cell and act as an adaptor between ubiquitinated proteins and molecular motors for the movement of the first ones to their degradation through the aggresome and autophagy pathway. In collaboration with A. Valenzuela-Fernandez (Tenerife, Spain), we recently showed that HDAC6 forms a complex with A3G , regardless of the presence of Vif, but that these proteins could compete for the degradation of A3G and regulate viral infectivity. The candidate will seek to identify, at the molecular level, domains of HDAC6 involved in this regulation, and to understand the relationship between HDAC6, A3G and Vif that leads not only to A3G protection towards its Vif-induced degradation (proteasome) but also to the autophagic degradation of Vif.
Altogether, this work should extend our knowledge on the mechanisms of cellular restriction of HIV -1, basis for the development of new inhibitors directed against this activity.

Wished skills: The candidate must have basic knowledge of molecular and cellular biology. Competences in virology will be appreciated. The search and analysis for information, through scientific publications, will be an essential skill, just like the knowledge of English. Experimentally speaking, skills in biochemistry and molecular biology are indispensable. Basic knowledge in cell culture will be strongly appreciated

Expertises which will be acquired during the training: The PhD candidate will be involved in a competitive project of research. He (she) will gain a strong expertise in molecular and cellular biology techniques and will apply recent imagery techniques. At the end of his/her thesis, he/she will also be expert in biochemistry, molecular virology and biophysics. Finally, the PhD candidate will have to present the results of his/her research at national and international scientific meetings and he/she should be able to write his/her work in English in order to get it published in international journals