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Journal of Virology, July 2008, p. 6935-6941, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.02599-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Blocking Antibody Access to Neutralizing Domains on Glycoproteins Involved in Entry as a Novel Mechanism of Immune Evasion by Herpes Simplex Virus Type 1 Glycoproteins C and E

Lauren M. Hook,^1, Jialing Huang,¹ Ming Jiang,^1, Richard Hodinka,² and Harvey M. Friedman^1*

Infectious Disease Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,¹ Clinical Virology Laboratory, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104²

Received 6 December 2007/ Accepted 7 May 2008

Herpes simplex virus type 1 (HSV-1) glycoprotein C (gC) blocks complement activation, and glycoprotein E (gE) interferes with IgG Fc-mediated activities. While evaluating gC- and gE-mediated immune evasion in human immunodeficiency virus (HIV)-HSV-1-coinfected subjects, we noted that antibody alone was more effective at neutralizing a strain with mutations in gC and gE (gC/gE) than a wild-type (WT) virus. This result was unexpected since gC and gE are postulated to interfere with complement-mediated neutralization. We used pooled human immunoglobulin G (IgG) from HIV-negative donors to confirm the results and evaluated mechanisms of the enhanced antibody neutralization. We demonstrated that differences in antibody neutralization cannot be attributed to the concentrations of HSV-1 glycoproteins on the two viruses or to the absence of an IgG Fc receptor on the gC/gE mutant virus or to enhanced neutralization of the mutant virus by antibodies that target only gB, gD, or gH/gL, which are the glycoproteins involved in virus entry. Since sera from HIV-infected subjects and pooled human IgG contain antibodies against multiple glycoproteins, we determined whether differences in neutralization become apparent when antibodies to gB, gD, or gH/gL are used in combination. Neutralization of the gC/gE mutant was greatly increased compared that of WT virus when any two of the antibodies against gB, gD, or gH/gL were used in combination. These results suggest that gC and gE on WT virus provide a shield against neutralizing antibodies that interfere with gB-gD, gB-gH/gL, or gD-gH/gL interactions and that one function of virus neutralization is to prevent interactions between these glycoproteins.

Published ahead of print on 14 May 2008.

Current address: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006.

Current address: Nucleic Acid/Protein Research Core Facility, The Children's Hospital of Philadelphia, 906B Abramson Building, 34th St. and Civic Center Boulevard, Philadelphia, PA 19104.