Abstract
Human cytomegalovirus (HCMV), a dsDNA, enveloped virus, is a ubiquitous pathogen that establishes lifelong latent infections and caused disease in persons with compromised immune systems, e.g., organ transplant recipients or AIDS patients. HCMV is also a leading cause of congenital viral infections in newborns. Entry of HCMV into cells requires the conserved glycoprotein B (gB), thought to function as a fusogen and reported to bind signaling receptors. gB also elicits a strong immune response in humans and induces the production of neutralizing antibodies although most anti-gB Abs are non-neutralizing. Here, we report the crystal structure of the HCMV gB ectodomain determined to 3.6-Å resolution, which is the first atomic-level structure of any betaherpesvirus glycoprotein. The structure of HCMV gB resembles the postfusion structures of HSV-1 and EBV homologs, establishing it as a new member of the class III viral fusogens. Despite structural similarities, each gB has a unique domain arrangement, demonstrating structural plasticity of gB that may accommodate virus-specific functional requirements. The structure illustrates how extensive glycosylation of the gB ectodomain influences antibody recognition. Antigenic sites that elicit neutralizing antibodies are more heavily glycosylated than those that elicit non-neutralizing antibodies, which suggest that HCMV gB uses glycans to shield neutralizing epitopes while exposing non-neutralizing epitopes. This glycosylation pattern may have evolved to direct the immune response towards generation of non-neutralizing antibodies thus helping HCMV to avoid clearance. HCMV gB structure provides a starting point for elucidation of its antigenic and immunogenic properties and aid in the design of recombinant vaccines and monoclonal antibody therapies.
Highlights
Herpesviruses are double-stranded DNA, enveloped viruses that cause lifelong latent infections
The structure is expected to aid in the development of a Human cytomegalovirus (HCMV) vaccine and monoclonal antibody therapies
HCMV is capable of causing disease in the immunocompromised including such symptoms as gastrointestinal ulceration, hepatitis, pneumonitis or retinitis in solid organ transplant patients [2] and retinitis in patients with AIDS, which can lead to blindness [2]
Summary
Herpesviruses are double-stranded DNA, enveloped viruses that cause lifelong latent infections. These viruses are divided into three subfamilies, alpha-, beta-, and gammaherpesviruses. While HCMV establishes lifelong latent infections, its reactivations are typically suppressed by competent immune systems. HCMV is capable of causing disease in the immunocompromised including such symptoms as gastrointestinal ulceration, hepatitis, pneumonitis or retinitis in solid organ transplant patients [2] and retinitis in patients with AIDS, which can lead to blindness [2]. Ganciclovir has associated toxicity and cannot be administered to some patients such as pregnant women [5]. Rising resistance to ganciclovir is a major concern [6, 7]. A better understanding of the immune response elicited by gB is needed to generate improved neutralizing monoclonal antibody (mAb) therapeutics and recombinant protein vaccines
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