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  Director : HOVANESSIAN Ara (arahovan@pasteur.fr)


  abstract

 

In order to clarify the mechanisms implicated in AIDS pathogenesis in relation to HIV infection, we are studying the different steps in the HIV infectious cycle, and particularly on the viral entry process. As interferon protects cells against virus infections, studies are carried out in order to understand its mechanism of action. In this respect, the major lines of research are: 1) HIV entry and its inhibitiion by the pseudopeptide HB-19 and the cytokine Midkine; 2) Role of IRF7 in the onset of the antiviral state; 3) Role of PKR in the mechanism of action of IFN 4) Molecular interactions between HCV and its cellular host.



  report

cale

The Anti-HIV Pseudopeptide HB-19 Binds the C-terminal End of Nucleolin and Prevents Anchorage of Virus Particles on Target Cells (S. Nisole, B. Krust, E. Said, A.G. Hovanessian)

The pseudopeptide HB-19 is a potent inhibitor of HIV infection in different CD4+ cell lines as well as in primary T lymphcytes and maccrophages. HB-19 binds the cell-surface-expressed nucleolin and blocks virus particle attachment on permissive cells. Here we show that cross-linking of surface bound HB-19 leads to capping of surface-nucleolin and its colocalization with HB-19 as revealed by confocal laser immunofluorescence microscopy. The use of various deletion constructs of the C-terminal part of nucleolin then permitted the identification of the extreme C-terminal end of nucleolin, containing repeats of the motif RGG, as the domain which binds HB-19. Finally, a synthetic peptide corresponding to this 63 amino acids was able to inhibit HIV infection at the stage of HIV attachment to cells, thus suggesting that this domain could be functional in the HIV anchorage process.

The anti-HIV pentameric pseudopeptide HB-19 is preferentially taken up in vivo by lymphoid organs where it forms a complex with nucleolin (B. Krust, A.G. Hovanessian in collaboration with L. Edelman)

Here, we have investigated the tissue distribution of the tritiated HB-19 using -radio imager whole body mapping in rats. A rapid, selective and stable distribution and accumulation of the systematically administered HB-19 was demonstrated within the spleen, liver, bone and kidney as soon as 5 min following its administration. No apparent uptake of HB-19 occurred in the brain and the muscle tissue. The elimination of HB-19 mainly occurred via renal glomerular filtration and most of the excreted radioactivity appeared to be HB-19 metabolites. Finally, injection of the biotin-labeled HB-19 pseudopeptide but not its control counterpart allowed the recovery of the HB-19/nucleolin complex from the liver, spleen, thymus, and bone marrow, thus indicating that the in vivo molecular target of HB-19 is surface nucleolin. Our results demonstrate the preferential uptake and stability of HB-19 in lymphoid organs that are the site of HIV propagation.

Anchorage of HIV on Permissive Cells Leads to Co-capping of Viral Particles with Surface Nucleolin at Membrane Raft Microdomains (S. Nisole, B. Krust, and A.G. Hovanessian)

The cross-linking of HIV particles on permissive cells results capping of HIV and its colocalization with clustered surface nucleolin, CD4, and CXCR4, but without affecting the organization of CD45. In addition, HIV particles and nucleolin co-cap with glycolipid-enriched membrane-microdomains (GEMs) containing ganglioside, and glycosylphosphatidylinositol-linked proteins CD90 and CD59, pointing out



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  personnel

  Office staff Researchers Scientific trainees Other personnel
 

HOVANESSIAN Ara

HOVANESSIAN Ara, CNRS/IP arahovan@pasteur.fr

KRUST Bernard, INSERM bkrust@pasteur.fr

MARIE Isabelle, IP imarie@pasteur.fr

MEURS Eliane, IP emeurs@pasteur.fr

BONNET Marion, PhD Student

CAILLAUD Alexandre PhD Student

NISOLE Sébastien, PhD Student

SAID Elias, PhD Student

ROBERT Nadine, Technician

SVAB Josette, Technician


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