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Journal of Virology, May 2008, p. 4612-4619, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02233-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hydrophobic Inactivation of Influenza Viruses Confers Preservation of Viral Structure with Enhanced Immunogenicity{triangledown}

Yossef Raviv,1,2* Robert Blumenthal,1 S. Mark Tompkins,3 Jennifer Humberd,3 Robert J. Hogan,4 and Mathias Viard1,2

Nanobiology Program, Center of Cancer Research, National Cancer Institute, National Institutes of Health,1 Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland,2 Department of Infectious Diseases, University of Georgia, Athens, Georgia,3 Department of Anatomy and Radiology, University of Georgia, Athens, Georgia4

Received 15 October 2007/ Accepted 15 February 2008

The use of inactivated influenza virus for the development of vaccines with broad heterosubtypic protection requires selective inactivation techniques that eliminate viral infectivity while preserving structural integrity. Here we tested if a hydrophobic inactivation approach reported for retroviruses could be applied to the influenza virus. By this approach, the transmembrane domains of viral envelope proteins are selectively targeted by the hydrophobic photoactivatable compound 1,5-iodonaphthyl-azide (INA). This probe partitions into the lipid bilayer of the viral envelope and upon far UV irradiation reacts selectively with membrane-embedded domains of proteins and lipids while the protein domains that localize outside the bilayer remain unaffected. INA treatment of influenza virus blocked infection in a dose-dependent manner without disrupting the virion or affecting neuraminidase activity. Moreover, the virus maintained the full activity in inducing pH-dependent lipid mixing, but pH-dependent redistribution of viral envelope proteins into the target cell membrane was completely blocked. These results indicate that INA selectively blocks fusion of the virus with the target cell membrane at the pore formation and expansion step. Using a murine model of influenza virus infection, INA-inactivated influenza virus induced potent anti-influenza virus serum antibody and T-cell responses, similar to live virus immunization, and protected against heterosubtypic challenge. INA treatment of influenza A virus produced a virus that is noninfectious, intact, and fully maintains the functional activity associated with the ectodomains of its two major envelope proteins, neuraminidase and hemagglutinin. When used as a vaccine given intranasally (i.n.), INA-inactivated influenza virus induced immune responses similar to live virus infection.

* Corresponding author. Mailing address: Building 469, Room 215, NCI-Frederick, Frederick, MD 21702. Phone: (301) 846-6522. Fax: (301) 846-6210. E-mail: yraviv{at}ncifcrf.gov

{triangledown} Published ahead of print on 27 February 2008.

Journal of Virology, May 2008, p. 4612-4619, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02233-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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