Infectivity Studies of Influenza Virus Hemagglutinin Receptor Binding Site Mutants in Mice

Infectivity Studies of Influenza Virus Hemagglutinin Receptor Binding Site Mutants in Mice ▿ Jeffrey Meisner 1 , Kristy J. Szretter 1 , 2 , Konrad C. Bradley 1 , William A. Langley 1 , Zhu-Nan Li 1 , Byeong-Jae Lee 1 , Sudha Thoennes 1 , Javier Martin 3 , John J. Skehel 4 , Rupert J. Russell 5 , Jacqueline M. Katz 2 , and David A. Steinhauer 1 , * 1 Emory University School of Medicine, 1510 Clifton Rd., Atlanta, Georgia 30322 2 Influenza Branch MS G-16, Centers for Disease Control, 1600 Clifton Rd., Atlanta, Georgia, 30333 3 Division of Virology, Nation Institute for Biological Standards and Controls, Blanche Lane, Potters Bar, Hertfordshire EN6 3QG, United Kingdom 4 National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom 5 School of Biology, University of St. Andrews, Fife KY16 9ST, United Kingdom ABSTRACT The replicative properties of influenza virus hemagglutinin (HA) mutants with altered receptor binding characteristics were analyzed following intranasal inoculation of mice. Among the mutants examined was a virus containing a Y98F substitution at a conserved position in the receptor binding site that leads to a 20-fold reduction in binding. This mutant can replicate as well as wild-type (WT) virus in MDCK cells and in embryonated chicken eggs but is highly attenuated in mice, exhibiting titers in lungs more than 1,000-fold lower than those of the WT. The capacity of the Y98F mutant to induce antibody responses and the structural locations of HA reversion mutations are examined.