Journal Article

Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine

Zhiqiang An, Xi He, Zhao Huang, Lin Xia, Fengsheng Li, Tong-Ming Fu, Ningyan Zhang, Danilo R. Casimiro, Adam C. Finnefrock, Eberhard Durr, Dai Wang, Daniel C. Freed, Weixu Meng, Amy S. Espeseth, John W. Shiver, Aimin Tang, Qi Tang

2013

Overview

Human cytomegalovirus (HCMV) can cause serious morbidity/mortality in transplant patients, and congenital HCMV infection can lead to birth defects. Developing an effective HCMV vaccine is a high medical priority. One of the challenges to the efforts has been our limited understanding of the viral antigens important for protective antibodies. Receptor-mediated viral entry to endothelial/epithelial cells requires a glycoprotein H (gH) complex comprising five viral proteins (gH, gL, UL128, UL130, and UL131). This gH complex is notably missing from HCMV laboratory strains as well as HCMV vaccines previously evaluated in the clinic. To support a unique vaccine concept based on the pentameric gH complex, we established a panel of 45 monoclonal antibodies (mAbs) from a rabbit immunized with an experimental vaccine virus in which the expression of the pentameric gH complex was restored. Over one-half (25 of 45) of the mAbs have neutralizing activity. Interestingly, affinity for an antibody to bind virions was not correlated with its ability to neutralize the virus. Genetic analysis of the 45 mAbs based on their heavy- and light-chain sequences identified at least 26 B-cell linage groups characterized by distinct binding or neutralizing properties. Moreover, neutralizing antibodies possessed longer complementarity-determining region 3 for both heavy and light chains than those with no neutralizing activity. Importantly, potent neutralizing mAbs reacted to the pentameric gH complex but not to gB. Thus, the pentameric gH complex is the primary target for antiviral antibodies by vaccination.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Antibodies, Monoclonal - genetics / Antibodies, Monoclonal - immunology / Antibodies, Neutralizing - genetics / Antibodies, Neutralizing - immunology / Antibodies, Viral - genetics / Antibodies, Viral - immunology / antibody affinity / Antigens / B-lymphocytes / Biological Sciences / Birth defects / Complementarity Determining Regions - genetics / Complementarity Determining Regions - immunology / congenital abnormalities / Cytomegalovirus - genetics / Cytomegalovirus - immunology / Cytomegalovirus Infections - genetics / Cytomegalovirus Infections - immunology / Cytomegalovirus Infections - prevention & control / Cytomegalovirus Vaccines - genetics / Cytomegalovirus Vaccines - immunology / epithelial cells / Female / Gene expression / genetic techniques and protocols / Glycoproteins / Human betaherpesvirus 5 / Human cytomegalovirus / Humans / Immunization / Immunoglobulin Heavy Chains - genetics / Immunoglobulin Heavy Chains - immunology / Immunoglobulin Light Chains - genetics / Immunoglobulin Light Chains - immunology / Immunology / Membrane Glycoproteins - genetics / Membrane Glycoproteins - immunology / Monoclonal antibodies / morbidity / mortality / Multiprotein Complexes - genetics / Multiprotein Complexes - immunology / Neutralization / neutralizing antibodies / patients / PNAS Plus / Rabbits / vaccination / Vaccines / viral antigens / Viral Envelope Proteins - genetics / Viral Envelope Proteins - immunology / viral proteins / virion / Viruses