Organization Chart

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HKU-Pasteur Research Centre LtdBoard of Directors

Scientific Advisory Board

Chief Executive Officer &

Scientific Director

Teaching

Viral InteractomeSARS-CoV

Avian Influenza

Innate ImmunologyVirus-NK cells Interactions

Adaptative ImmunitySARS-CoV

Viral EntrySARS-CoV (Antibody-Dependent

Enhancement )Avian Influenza

Screening PlatformVirus-Host Interactions

Screening Technology & AssayDevelopment

High-Content High-ThroughputScreening

Drug DiscoveryHIV

DengueAvian Influenza

Sero-epidemiologyAvian Influenza

Pasteur-Asia Virology Courses

Croucher-Pasteur Exchange Programme

University of Hong KongFinancial Office

Communication & Public RelationsOffice

Institut PasteurBusiness Development

& Technology Transfert Department

Viral Infection & Immunity

Viral Assembly & BuddingSARS-CoV

Dengue Fever

Virus / Cell BiologyDr Béatrice NAL-ROGIERDr Dong Jiang TANGDr François KIENDr Pei Gang WANGMs Jane TSEMr Lewis SUIMs Kid CHUMr Jean MILLETMr Michael TEOH

TeachingDr Roberto BRUZZONEPr Malik PEIRISDr Noël TORDO (Institut Pasteur)

Virus / ImmunolgyDr Joanna HODr Martial JAUMEMs Isabelle DUTRYMr Ping Hung LIMr Jason KAMMr Mateusz KUDELKO

Screening PlatformDr Jean-Michel GARCIAMs Nadège LAGARDEMs Joyce CHOIMr Jimmy LAI

Organization & Staff

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Chief Excutive OfficerDr Roberto BRUZZONE

Scientific DirectorPr Malik PEIRIS

AdministrationMs Anne LIMs Bella TSENGMr Simon LAM

Virus-Host Interactions

During millions of years of co-evolution, viruses and host cells have adapted themselves to each others. On the one hand, viruses are clever cell biologists and have developed amazing strategies to exploit cellular machineries like vesicular and protein trafficking, biosynthesis and sorting machineries. On the other hand, cells have reacted to viral invasions by developing innate defense mechanisms and by expressing restriction factors for viral replication.

The understanding of cross-talk processes between viruses and host cells is a must to identify new targets for future antiviral therapeutic approaches.

Cellular "Interactomes" for viral structural proteins

In order to identify new cellular factors able to enhance or restrict early (entry) and late (assembly and budding) stages of viral infections large-scale genomic approaches like yeast-2-hybrid (Y2H) and siRNA library screens are used. A particular interest is given to Dengue, Highly Pathogenic Avian Influenza H5N1 and SARS viruses.

Our approaches combine fundamental approaches of biology (molecular and cellular biology, protein-protein interaction, Y2H, siRNA technology), virology (biochemistry of viral proteins, pseudotyped viruses, virus-like particles) and advanced imaging processes (confocal microscopy, video imaging).

Contact: Dr Béatrice Nal-Rogier Tel: (852) 2816 8422 Email: bnal@hku.hk

Virus / Cell Biology

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The immune system protects, through a coordinated set of mechanisms, the integrity of the host from diverse threats such as pathogens and tumor cells. The system can be broadly divided into two major components: innate and adaptive immunity.

Understanding Innate Immunity during Viral Infection

Cells of the innate immunity system such as Natural Killer (NK), macrophages, and Dendritic Cells (DC) are the frontline players in the event of a viral attack. H5N1 Avian Influenza, SARS coronavirus (SARS-CoV), and Dengue virus (DV) are known to have rapid detrimental effects to infected humans, thus suggesting that the innate response may play a crucial role in the fight against these pathogens. Therefore, it is important to understand the precise mechanisms involved.

Our work focuses on understanding the interactions between activating receptors of NK cells and viral envelop proteins of Influenza, SARS-CoV, and DV. Our projects are at the interface of fundamental and applied research with the aim of contributing to the identification of novel therapeutic applications.

Contact: Dr Joanna Ho Tel: (852) 2816 8423 Email: joannaho@hku.hk

Stimulating Adaptative Immunity: safety concerns

The host responds to infecting viruses by activating its innate immune system and mounting virus-specific humoral and cellular immune responses. These responses are aimed at controlling viral replication and eliminating the infecting virus from the host.

In some circumstances, however, the immune system can actually enhance viral infection by exploiting humoral responses for a more efficient entry into target cells, as it has been shown for some viruses.

One such mechanisms, termed antibody-dependent enhancement (ADE) of viral infection has been already observed for the coronavirus family, which the SARS-CoV belongs to.

From early SARS outbreaks, HKU-Pasteur Research Centre has been engaged in the development of a safe vaccine candidate, investigating both beneficial but also deleterious outcome of SARS vaccination.

Contact: Dr Martial Jaume Tel: (852) 2816 8426 Email: breizh@hku.hk

Our multidisciplinary projects are at the interface of immunology (animal immunization, analysis of the innate and humoral immune response, Fc and NK cell-activating receptors, monoclonal antibody production), cell biology (cell signaling, protein-protein interactions) and virology (viral envelope glycoproteins, alternative viral entry mechanism, pseudotyped virus).

Virus / Immunology

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HKU-Pasteur Research Centre is developing new tools based on flow cytometry technology that will lead to enhanced identification of cellular factors governing virus replication as well as virus entry inhibitors and the analysis of the sero-prevalence of virus infection in the general population.

A flexible ...

We are using pseudotyped lentiviral vectors expressing different reporter genes. These pseudotyped viral particles have been generated for HIV, SARS-CoV and Highly Pathogenic Avian Influenza H5N1. The specificity of infection is conferred by the heterologous viral surface glycoprotein used to pseudotype the lentiviral particles. Using this flexible system, we can study viral entry at different levels:

l Drug Discovery: identification of viral entry inhibitors from synthetic compound- and Traditional Chinese Medicine-based libraries;

l Sero-epidemiology: rapid and sensitive identification of neutralizing antibodies against a given pathogen as an indication of exposure during an epidemic;

l Virus / Cell Biology: identification of cellular partners involved in viral entry by specific gene knock-down using a siRNA library.

... and yet powerful tool

All these applications have in common that they require the screening of large libraries of molecules. We have developed a high throughput platform to support these applications. Since most of the time the screened samples are in very limited amount, we are developing a high content screening to get as much information as possible per sample tested. This approach allows, for instance, to obtain at the same time information about cell cytotoxicity and virus entry inhibition in drug discovery, or to study sero-epidemiology for different subtypes of influenza virus.

Our approaches combine molecular biology with pseudotyped viruses, high throughput flow cytometry, statistical analysis and assay development. Our projects are at the interface between virology, immunology, technology and chemistry.

Contact: Dr Jean-Michel Garcia Tel: (852) 2816 8417 Email: jmgarcia@hku.hk

Screening Platform

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2007Buchy P., Mardy S., Vong S., Toyoda T., Aubin J. T., Miller M., Touch S., Sovann L., Dufourcq J. B., Richner B, Tu P. V., Tien N. T., Lim W., Peiris J. S. and Van der Werf S.

Influenza A/H5N1 virus infection in humans in Cambodia.

J Clin Virol 2007, 39(3):164-168

Chui S. S., Peiris J. S., Chan K. H., Wong W. H. and Lau Y. L.

Immunogenicity and safety of intradermal influenza immunization at a reduced dose in healthy children.

Paediatrics 2007, 119(6):1076-1082

Peiris J. S. M., de Jong M. D., and Guan Y.

Avian Influenza Virus (H5N1): a Threat to Human Health.

Clin Microbiol Rev 2007, 20(2): 243-267.

Nefkens I., Garcia JM., Chu S. L., Lagarde N., Nicholls J. ,Tang D. J., Peiris M., Buchy P., and Altmeyer R.

Hemagglutinin pseudotyped lentiviral particles: Characterization of a new method for avian H5N1 influenza sero-diagnosis.

J Clin Virol 2007 April 3; [Epub ahead of print].

2006Kam Y. W., Kien F., Roberts A., Cheung Y. C., Lamirande E. W., Vogel L., Chu S. L., Tse J., Subbarao K., Peiris M., Nal B., and Altmeyer R.

Antibodies against trimeric S glycoprotein protect against SARS-CoV challenge despite their capacity to mediate FcγRII-dependent entry into B cells in vitro.

Vaccine 2006 August 22; [Epub ahead of print].

2005Fang G., Ho C., Qiu Y., Cubas V., Yu Z., Cabau C., Cheung, F., Moszer I., and Danchin A.

Specialized microbial databases for inductive exploration of microbial genome sequences.

BMC Genomics, 2005. 6 (1): p. 14

Nal-Rogier B.T.M., Chan C.M., Kien F.S., Siu Y.L., Tse K.S., Chu S.L., Kam Y.W., Staropoli I., Crescenzo-Chaigne B., Escriou N., van der Werf S., Yuen K.Y. and Altmeyer R.M.

Differential maturation and subcellular localization of severe acute respiratory syndrome coronavirus surface proteins S, M and E.

J Gen Virol. 2005, 86(Pt 5):1423-34.

Yap Y.L., Lam C.L., Girard L., Zhang X., Hernandez D., Gras R., Wang E., Chiu S. .W., Chung L.P., Lam W.K., Smith D.K., Minna J. .D., Danchin A. and Wong M.P.

Conserved transcription factor binding sites of cancer markers derived from primary lung adenocarcinoma microarrays.

Nucleic Acids Res (2005), 33(1):409-21.

Erratum in Nucleic Acids Res. 2005;33(8):2764.

Zhang X., Yap Y.L. and Danchin A.L.M.

A Testing the hypothesis of a recombinant origin of the SARS-associated coronavirus.

Arch Virol (2005), 150: 1-20.

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Zhang X., Yap Y.L. and Altmeyer R.M.

Generation of predictive pharmacophore model for SARS-Coronavirus main proteinase.

Eur J Med Chem. 2005 Jan; 40(1):57-62.

2004Altmeyer, R . et al. 2004.

U.S. provisional patent application.

A process for vaccinating eucaryotic hosts and for protecting against SARS-CoV infection.

Altmeyer R.

Virus attachment and entry offer numerous targets for antiviral therapy.

Curr Pharm Des. 2004; 10(30):3701-12. Review.

Lozach P.Y., Amara A., Bartosch B., Virelizier J.-L., Arenzana-Seisdedos F., Cosset F.-L. and Altmeyer R.

C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles.

J Biol Chem. (2004), 279 (31):32035-45.

Sekowska A., Denervaud V., Ashida H., Michoud K., Haas D., Yokota A., and Danchin, A.

Bacterial variations on the methionine salvage pathway.

BMC Microbiol, 2004; 4 : p. 9.

Yap Y.L., Zhang X., Ling M.T., Wang X.H., Wong Y.C. and Danchin A.L.M.

Classification between normal and tumor tissues based on the pair-wise gene expression ratio.

BMC Cancer . 2004, 4: 72. (Publication No. : 95163).

Zhang X. and Yap Y.L.

Putative structure and function of ORF3 in SARS coronavirus.

J Mol Struct (2004), 715: 55-58.

Zhang X. and Yap Y.L.

The 3D structure analysis of SARS-CoV S1 protein reveals a link to influenza virus neuraminidase and implications for drug and antibody discovery.

J Mol Struct: Theochem (2004), 681: 137-141.

Nal-Rogier B.T.M., Chan C.M., Siu Y.L., Chu S.L. and Altmeyer R.M.

Biogenesis and subcellular localization of the SARS coronavirus surface proteins.

FASEB J (2004), 18 (8): C71-C71 Suppl.

Altmeyer, R., A. Amara, B. Bartosch, J. L. Virelizier, F. Arenzana-Seisdedos, F. L. Cosset, and P. Y. Lozach.

C-type Lectins L-SIGN and DC-SIGN Capture and Transmit Infectious Hepatitis C Virus Pseudotype Particles.

FASEB J (2004) 18:C31-C31.

Rocha E.P.C. and Danchin A.L.M.

An analysis of determinants of amino acids substitution rates in bacterial proteins.

Mol Biol Evol (2004), 21(1): 108-16.

Sekowska A., Denervaud V., Ashida H., Michoud K., Haas D., Yokota A. and Danchin A.L.M.

Bacterial variations on the methionine salvage pathway.

BMC Microbiol (2004), 4(1): 9.

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Wang Y., Eduardo P., Rocha C., Frederick C., Leung C.C. and Danchin A.L.M.

Cytosine methylation is not the major factor inducing CpG dinucleotide deficiency in bacterial genomes.

J Mol Evol (2004), 58(6): 692-700.

Zhang X. and Yap Y.L.

Exploring the binding mechanism of the main proteinase in SARS-associated coronavirus and its implication to anti-SARS drug design.

Bioorg Med Chem (2004), 12 (9): 2219-23.

Zhang X. and Yap Y.L.

Old drugs as lead compounds for a new disease? Binding analysis of SARS coronavirus main proteinase with HIV, psychotic and parasite drugs.

Bioorg Med Chem (2004), 12(10): 2517-2521.

Zhang X. and Yap Y.L.

Structural similarity between HIV-1 gp41 and SARS-CoV S2 proteins suggests an analogous membrane fusion mechanism.

J Mol Struct: Theochem (2004), 677: 73-76.

2003Yap Y.L., Zhang X. and Danchin A.L.M.

Relationship of SARS-CoV to Other Pathogenic RNA Viruses explored by tetranucleotide usage profiling.

BMC Bioinformatics (2003), 4(1): 43.

Zhang Y.Q., Ren S.X., Li H.L., Wang Y.X., Fu G., Yang J., Qin Z.Q., Miao Y.G., Wang W.Y., Chen R.S., Shen Y., Chen Z., Yuan Z.H., Zhao G.P., Qu D., Danchin A.L.M. and Wen Y.M.

Genome-based analysis of virulence genes in a non-biofilm-forming Staphylococcus epidermidis strain.

Mol Microbiol (2003), 49(6): 1577-93.

Rocha E.P.C. and Danchin A.L.M.

Essentiality, not expressiveness, drives gene-strand bias in bacteria.

Nat Genet (2003), 34(4): 377-8.

Rocha E.P.C., Fralick J., Vediyappan G., Danchin A.L.M. and Norris V.

A strand-specific model for chromosome segregation in bacteria.

Mol Microbiol . 2003, 49(4): 895-903.

Tendeng C., Krin E., Soutourina O.A., Marin A., Danchin A.L.M. and Bertin P.N.

A Novel H-NS-like protein from an antarctic psychrophilic bacterium reveals a crucial role for the N-terminal domain in thermal stability.

J Biol Chem (2003), 278(21): 18754-60.

Tosato V., Gjuracic K., Vlahovicek K., Pongor S., Danchin A.L.M. and Bruschi C.V.

The DNA secondary structure of the Bacillus subtilis genome.

FEMS Microbiol Lett (2003), 218(1): 23-30.

Yuen K.Y., Pascal G., Wong S.S.Y., Glaser P., Woo P.C.Y., Kunst F., Cai J., Leung E.Y.L., Medigue C. and Danchin A.L.M.

Exploring the Penicillium marneffei genome.

Arch Microbiol (2003), 179: 339-353.

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