Gillian Air  /  Sanjay Bidichandani  /  Robert Broyles
  Paul DeAngelis  /  Jay Hanas  /  Martin Levine  /  Guangpu Li 

Jialing Lin  /  Hiroyuki Matsumoto  / Blaine Mooers /  Ann Louise Olson 

Karla Rodgers  /  Robert Steinberg  /  Leon Unger  /  Paul Weigel   /  Christopher West 

Molecular biology of influenza virus; mechanisms of antigenic variation; development of antiviral agents.

Influenza occurs every winter, usually peaking in January in the northern hemisphere. Approximately 20,000 deaths in the US per year are attributed to influenza, many among elderly patients who have medical conditions that increase the likelihood of complications from influenza. Influenza is a significant disease in all age groups; an acute febrile illness with myalgia, headache, fever and cough. A rule-of-thumb for distinguishing influenza from other respiratory virus infections is that if you really can't get out of bed, it's probably flu. The acute stage lasts about 3 days, but cough and malaise may last for some weeks.

The most commonly used influenza vaccine is the "subunit" formulation (purified surface  antigens).  It is safe  although  somewhat variable in effect, depending on the age and immunocompetence of the vaccinee as well as the similarity of the  vaccine  strain  to  the   circulating viruses. An attenuated live vaccine has recently become available, with similar efficacy. Vaccine  manufacture is complicated  by the  need  to  update  the components every year in response to antigenic variation. Strains currently circulating in the human population are classified serologically as type A (H1N1, H3N2) and type B. “H” and “N” refer to the viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA).

Influenza viruses undergo progressive antigenic drift; an accumulation of mutations that alter antigenic properties. Occasionally there is an antigenic shift, introducing new antigens into human influenza viruses, so the current epidemic of H5N1 viruses in birds in southeast Asia is being watched very carefully.

Our research has two branches, one to find ways of designing better vaccines, and the second to investigate how the virus gains entry into cells and how infection might be blocked by antiviral drugs. 

Much of our work has been focused on the sialic-acid cleaving enzyme neuraminidase (NA). Crystal structures are available of NA itself and also of NA complexed with antibodies or inhibitors. Using monoclonal antibodies, we have determined the extent and nature of epitopes on the NA, how antibodies bind to these to inhibit enzyme activity and hence virus spread, and how the virus can mutate to escape from neutralizing antibodies. We have been applying these results to analyze the quality as well as quantity of antibodies present in human sera after influenza vaccination.

We are also involved in projects to design new NA inhibitors, and to identify receptors on the cell surface that facilitate virus infection with the idea of blocking that process with new drugs. It has been known for many years that the primary receptor for influenza is sialic acid, but our recent work has shown that the pattern of recognition for sialic acids and their neighboring sugars is more complex than originally thought.

Selected Publications:                         [Search Pubmed]

Air, G. M., and West, J. T. (in press). Antigenic Variation. In "Encyclopedia of Virology" Third ed. (B. W. Mahy, and M. van Regenmortel, Eds.). Elsevier.

Amonsen, M., Smith, D. F., Cummings, R. D., and Air, G. M. (2007). Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with {alpha}2-3 linked sialic acid that are distinct from those bound by H5 avian influenza hemagglutinin. J Virol 81:8341-8345.

Gulati, U., Keitel, W. A., and Air, G. M. (2007). Increased antibodies against unfolded viral antigens in the elderly after influenza vaccination. Influenza and Other Respiratory Viruses in press.

Kumari, K., Gulati, S., Smith, D. F., Gulati, U., Cummings, R. D., and Air, G. M. (2007). Receptor binding specificity of recent human H3N2 influenza viruses. Virol J 4:1-12.

Lee, J. T., and Air, G. M. (2006). Interaction between a 1998 human influenza virus N2 neuraminidase and monoclonal antibody Mem5. Virology 345:424-433.

Venkatramani, L., Bochkareva, E., Lee, J. T., Gulati, U., Laver, W. G., Bochkarev, A., and Air, G. M. (2006). An epidemiologically significant epitope of a 1998 human influenza virus neuraminidase forms a highly hydrated interface in the NA-antibody complex. J. Mol. Biol. 356:651-663 (cover picture).

Gulati, U., Kumari, K., Wu, W., Keitel, W.A., and Air, G.M. (2005) Amount and avidity of serum antibodies against native glycoproteins and denatured virus after repeated influenza whole-virus vaccination. Vaccine 23:1414-1425.

Gulati, U., Wu, W., Gulati, S., Kumari, K., Waner, J., and Air, G. (2005). Mismatched hemagglutinin and neuraminidase activities in recent human H3N2 influenza viruses. Virology 339:12-20.

Wu, W., and Air, G.M. (2004) Binding of influenza viruses to sialic acids: reassortant viruses with A/NWS/33 hemagglutinin bind to a2,8-linked sialic acid. Virology 325:340-350.

Lommer, B.S., Ali, S.M., Bajpai, S.N., Brouillette, W.J., Air, G.M., and Luo, M. (2003) A benzoic acid inhibitor induces a novel conformational change in the active site of influenza B virus neuraminidase. Acta Cryst. D 60:1017-1023.

Lee, J.T., and Air, G.M. (2002) Contacts between influenza N9 neuraminidase and monoclonal antibody NC10. Virology 300:255-268.

Gulati, U., Hwang, C.-C., Venkatramani, L., Gulati, S., Stray, S.J., Lee, J.T., Laver, W.G., Bochkarev, A., Zlotnick, A., and Air, G.M. (2002) Antibody epitopes on the neuraminidase of a recent H3N2 influenza virus (A/Memphis/31/98). J. Virol. 76:12274-12280.

Stray, S.J., and Air, G.M. (2001) Apoptosis by influenza viruses correlates with efficiency of viral mRNA synthesis. Virus Res. 77:3-17.

Stray, S.J., Cummings, R.D., and Air, G.M. (2000) Influenza virus infection of desialylated cells. Glycobiology 10:649-658.

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