Our activities on influenza viruses (IVs), SARS coronavirus (SARS-CoV), hepatitis C virus (HCV) and GB virus B (GBV-B), include studies of the molecular evolution, expression and replication of the viral genomes, particle morphogenesis, analysis of virus host interactions and evaluation of vaccines and antiviral candidates.

Evolution of influenza viruses. Surveillance activities of human IVs by the National Influenza Center (Northern France), were focused on the pandemic H1N1 2009 virus, particularly from severe cases. The global pattern of IVs circulation in waterbirds in the Camargue area was extended to wild boars (coll M. Gauthier-Clerc, Tour du Valat, F. Renaud, IRD/CNRS Montpellier).

Antivirals. A mutation in the neuraminidase (NA) of the H1N1(2009) virus conferring cross-resistance to oseltamivir and zanamivir was identified. The mechanisms underlying natural resistance to the currently available neuraminidase inhibitors were explored, and new sialic derivatives targeting specifically the group 1 neuraminidases were tested (coll M von Itzstein, Griffith University, Australia). The impact of genetic variations on the enzymatic characteristics of the neuraminidase (NA) of H1N1 2009 and H5N1 viruses were studied.

Signals at the extremities of genomic IV segments. Exchange of the non-conserved non-coding sequences of type A and C IVs viral RNAs revealed that type specific determinants differ between segments.

Determinants of influenza virus cross-species transmission and adaptation. The impact of genetic variations in the neuraminidase and the polymerase complex on the viral host-range were studied, using cell culture and animal models (coll D. Marc, INRA-Tours, R. Volmer INRA-ENVT). Molecular interactions between viral ribonucleoproteins and the host cell were analyzed by combining biochemical, genetic and imaging approaches (coll Y. Jacob, J.L. Jestin, IP Paris S. Cusack, EMBL-Grenoble).

SARS-CoV and IV H5N1 vaccine candidates. Evaluating the immunogenicity of soluble forms of the spike protein (Ssol) of SARS-CoV or of the IV H5N1 glycoproteins a protective role of the NA was found. Protective immune responses induced by recombinant viral vectors expressing the S protein of SARS-CoV or the H5 of H5N1 were further studied in hamsters and mice, respectively (coll. P. Marianneau, UBIVE, Lyon, P. Charneau - M. Huerre F. Tangy, IP Paris). Cross-reactive antigenic properties of the NA of H5N1 and H1N1 2009 viruses were studied.

Hepacivirus (HCV, GBV-B) replication. Using both HCV and the closely-related, primate hepatotropic virus GBV-B in cell culture systems and primate model, we identified molecular determinants and interactions involved in genome replication and virus assembly (coll. B.A. Malcolm, Tibotec, Belgium; R.E Lanford, SFBR, S.M. Lemon, UTMB, USA). Our current research addresses mechanisms of hepacivirus morphogenesis using functional, structural and imaging approaches, with a focus on the role and specificity of viral nonstructural proteins in this process (coll. F. Penin, IBCP, Lyon, D. Moradpour, Univ. Lausanne, Suisse, J-M. Betton, IP Paris).

Keywords: Influenza, respiratory viruses, vaccine, polymerase, host factors, evolution, antivirals, hepatitis, replication, hepacivirus, assembly

Rudrawar S, Dyason JC, Rameix-Welti MA, Rose FJ, Kerry PS, Russell RJ, van der Werf S, Thomson RJ, Naffakh N, von Itzstein M. (2010) Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase. Nat Commun. 2010 Nov;1(8):113. Epub 2010 Nov 16.PMID: 21081911 (PubMed - in process)

Munier S, Larcher T, Cormier-Aline F, Soubieux D, Su B, Guigand L, Labrosse B, Cherel Y, Quéré P, Marc D, Naffakh N. A genetically engineered waterfowl influenza virus with a deletion in the stalk of the neuraminidase has increased virulence for chickens. J Virol. 2010 Jan;84(2):940-52. Epub 2009 Nov 4.PMID: 19889765 (PubMed - indexed for MEDLINE)

Buchy P, Fourment M, Mardy S, Sorn S, Holl D, Ly S,

Vong S, Enouf V, Peiris JS, van der Werf S. (2009) Molecular epidemiology of clade 1 influenza A viruses (H5N1), southern indochina peninsula, 2004-2007. Emerg Infect Dis. 2009 Oct;15(10):1641-4.

L. Warter*, L. Cohen*, Y. Benureau, D. Chavez, Y. Yang, F. Bodola, S.M. Lemon, C. Traboni, R.E. Lanford and A. Martin (2009). A cooperative interaction between nontranslated RNA sequences and NS5A protein promotes in vivo fitness of a chimeric hepatitis C/GB-B virus. PLoS One. 2009;4(2):e4419. Epub 2009 Feb 10.

Callendret B., V. Lorin, P. Charneau, P. Marianneau, H. Contamin, J-M. Betton, S. van der Werf and N. Escriou. (2007) Heterologous viral RNA export elements improve expression of severe acute respiratory syndrome (SARS) coronavirus spike protein and protective efficacy of DNA vaccines against SARS. Virology 5;363(2):288-302.