Complete protection of mice against lethal murine cytomegalovirus challenge by immunization with DNA vaccines encoding envelope glycoprotein complex III antigens gH, gL and gO.

Huadong Wang,Zhenyuan Xie,Wenjie Zhang,Chaoyang Huang,Ze Chen,Fang Fang,Jinrong Dong,Xueying Liu,Yanfeng Yao,Matthias Johannes Schnell

doi:10.1371/journal.pone.0119964

Abstract

Human cytomegalovirus infects the majority of humanity which may lead to severe morbidity and mortality in newborns and immunocompromised adults. Humoral and cellular immunity are critical for controlling CMV infection. HCMV envelope glycoprotein complexes (gC I, II, III) represent major antigenic targets of antiviral immune responses. The gCIII complex is comprised of three glycoproteins, gH, gL, and gO. In the present study, DNA vaccines expressing the murine cytomegalovirus homologs of the gH, gL, and gO proteins were evaluated for protection against lethal MCMV infection in the mouse model. The results demonstrated that gH, gL, or gO single gene immunization could not yet offer good protection, whereas co-vaccination strategy apparently showed effects superior to separate immunization. Twice immunization with gH/gL/gO pDNAs could provide mice complete protection against lethal salivary gland-derived MCMV (SG-MCMV) challenge, while thrice immunization with pgH/pgL, pgH/pgO or pgL/pgO could not provide full protection. Co-vaccination with gH, gL and gO pDNAs elicited robust neutralizing antibody and cellular immune responses. Moreover, full protection was also achieved by simply passive immunization with anti-gH/gL/gO sera. These data demonstrated that gCIII complex antigens had fine immunogenicity and might be a promising candidate for the development of HCMV vaccines.

Highlights

Human cytomegalovirus (HCMV), a beta herpesvirus, is a ubiquitous large enveloped virus that infects 50 to 100% of the adult population worldwide [1]
A ~250 kDa protein band was detected, which should be the heterotrimer formed by gH, gL and gO proteins, and the size was consistent with the complex detected by Western blot in Murine cytomegalovirus (MCMV) infected 3T3 cells
For virus infected 3T3 cells (Fig. 2B), three proteins were mainly localized in juxtanuclear regions and were not present in the nucleus, which was consistent with the immunofluorescence observations of HCMV infected cells reported by Theiler et al [18]

Summary

Introduction

Human cytomegalovirus (HCMV), a beta herpesvirus, is a ubiquitous large enveloped virus that infects 50 to 100% of the adult population worldwide [1]. Fouts et al analyzed anti-CMV hyperimmuneglobulin (Cytogam) and found that neutralizing antibodies in sera from natural HCMV infections mainly targeted the protein complexes consisting of gH-gL, i.e., the heterologous pentamer gH/gL/UL128/UL130/UL131 and the gH/gL/gO complex, instead of the gB protein [13]. This suggests that the gH-gL complexes are the primary targets of the host’s neutralizing antibody response against HCMV infection. We investigated the immunogenicity and protective efficacy of MCMV gCIII antigens delivered in the form of DNA vaccine. The results demonstrated that gH/gL/gO complex had fine immunogenicity and could provide mice complete protection against lethal SG-MCMV challenge

Results

Discussion

Ethics statement