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Random Mutagenesis of the Gene Encoding a Viral Ligand for Multiple Cell Entry Receptors to Obtain Viral Mutants Altered for Receptor Usage
Miri Yoon and Patricia G. Spear
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 49 (Dec. 7, 2004), pp. 17252-17257
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3373992
Page Count: 6
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Herpes simplex virus type 1 (HSV-1) can enter cells expressing any one of multiple entry receptors, including the herpesvirus entry mediator (HVEM), nectin-1, and sites in heparan sulfate generated by specific 3-O-sulfotransferases. The viral ligand for these receptors is glycoprotein D (gD). To define structural requirements for functional interactions of gD with its receptors and to obtain viral mutants altered for receptor usage, we generated a library of HSV-1 mutants with random mutations in the gD gene. Viral isolates selected on a monkey cell line (Vero) were screened for the loss of ability to infect cells expressing each of the HSV-1 receptors. The 10 HSV-1 mutants obtained had 12 mutations in gD, affecting 11 amino acids. All mutations reduced or abrogated viral entry through HVEM and 3-O-sulfated heparan sulfate, indicating that similar features of gD are critical for functional interactions with both these receptors. None of the mutations reduced viral entry through nectin-1, whereas a subset of the mutations conferred ability to use nectin-2 as an entry receptor. These and other results show that features of gD, including conformation of the N terminus, critical for functional interactions with HVEM/3-O-sulfated heparan sulfate, differ from those critical for interactions with nectin-1.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences