Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response

Urban, Margit; Klein, Melissa J.; Wj, Britt; HAßFURTHER, E.; Mach, Michael

doi:10.1099/0022-1317-77-7-1537

Cited by 105 publications

(66 citation statements)

References 45 publications

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“…Protein alignment of CMV strain VR1814 to 10 CMV strains isolated from geographically distinct regions demonstrated diversity in all of the CMV glycoproteins, including the UL128, UL130, and UL131a proteins, with the greatest diversity appearing in gN and gO (Table 3). The natural humoral immune response to CMV primarily induces antibodies directed against gB; however, antibodies targeting gM/gN and gH/gL have also been identified (109,134,135). Recent work also revealed the exquisite potency of human-derived monoclonal antibodies (MAbs) that target the PC in blocking infection of epithelial, endothelial, and monocytic cells (111,136,137).…”

Section: Strain Polymorphism Contributes To Immune Evasionmentioning

confidence: 99%

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Gardner

Tortorella

2016

Microbiol Mol Biol Rev

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SUMMARYThe prototypic herpesvirus human cytomegalovirus (CMV) exhibits the extraordinary ability to establish latency and maintain a chronic infection throughout the life of its human host. This is even more remarkable considering the robust adaptive immune response elicited by infection and reactivation from latency. In addition to the ability of CMV to exist in a quiescent latent state, its persistence is enabled by a large repertoire of viral proteins that subvert immune defense mechanisms, such as NK cell activation and major histocompatibility complex antigen presentation, within the cell. However, dissemination outside the cell presents a unique existential challenge to the CMV virion, which is studded with antigenic glycoprotein complexes targeted by a potent neutralizing antibody response. The CMV virion envelope proteins, which are critical mediators of cell attachment and entry, possess various characteristics that can mitigate the humoral immune response and prevent viral clearance. Here we review the CMV glycoprotein complexes crucial for cell attachment and entry and propose inherent properties of these proteins involved in evading the CMV humoral immune response. These include viral glycoprotein polymorphism, epitope competition, Fc receptor-mediated endocytosis, glycan shielding, and cell-to-cell spread. The consequences of CMV virion glycoprotein-mediated immune evasion have a major impact on persistence of the virus in the population, and a comprehensive understanding of these evasion strategies will assist in designing effective CMV biologics and vaccines to limit CMV-associated disease.

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Section: Strain Polymorphism Contributes To Immune Evasionmentioning

confidence: 99%

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Gardner

Tortorella

2016

Microbiol Mol Biol Rev

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“…By contrast, coexpression of gB, gH, and gL triggers syncytium formation due to cell-cell fusion (E. R. Kinzler and T. Compton, submitted for publication). Both gB and gH are highly antigenic in CMV-infected individuals, and many antibodies directed against these two glycoproteins are neutralizing to CMV, blocking infection at the level of entry (3,9,27,31). To date, molecular details underlying the mechanism of CMV entry into host cells remain elusive.…”

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confidence: 99%

Coiled-Coil Domains in Glycoproteins B and H Are Involved in Human Cytomegalovirus Membrane Fusion

Lopper

Compton

2004

J Virol

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Human cytomegalovirus (CMV) utilizes a complex route of entry into cells that involves multiple interactions between viral envelope proteins and cellular receptors. Three conserved viral glycoproteins, gB, gH, and gL, are required for CMV-mediated membrane fusion, but little is known of how these proteins cooperate during entry (E. R. Kinzler and T. Compton, submitted for publication). The goal of this study was to begin defining the molecular mechanisms that underlie membrane fusion mediated by herpesviruses. We identified heptad repeat sequences predicted to form alpha-helical coiled coils in two glycoproteins required for fusion, gB and gH. Peptides derived from gB and gH containing the heptad repeat sequences inhibited virus entry when introduced coincident with virus inoculation onto cells or when mixed with virus prior to inoculation. Neither peptide affected binding of CMV to fibroblasts, suggesting that the peptides inhibit membrane fusion. Both gB and gH coiled-coil peptides blocked entry of several laboratory-adapted and clinical strains of human CMV, but neither peptide affected entry of murine CMV or herpes simplex virus type 1 (HSV-1). Although murine CMV and HSV-1 gB and gH have heptad repeat regions, the ability of human CMV gB and gH peptides to inhibit virus entry correlates with the specific residues that comprise the heptad repeat region. The ability of gB and gH coiled-coil peptides to inhibit virus entry independently of cell contact suggests that the coiled-coil regions of gB and gH function differently from those of class I, single-component fusion proteins. Taken together, these data support a critical role for alpha-helical coiled coils in gB and gH in the entry pathway of CMV.Herpesviruses are structurally complex enveloped viruses displaying at least nine glycoproteins on their surface (4,10,13,15,16,28). Unlike orthomyxoviruses, paramyxoviruses, filoviruses, and retroviruses that use a single glycoprotein for membrane fusion, herpesviruses employ multicomponent membrane fusion machines that comprise at least three proteins, glycoprotein B (gB), glycoprotein H (gH), and glycoprotein L (gL) (11,24,29). Each glycoprotein involved is conserved among the Herpesviridae family, but little is known of their structures or how their interactions promote membrane fusion. In addition to the three conserved glycoproteins, gB, gH, and gL, some herpesviruses require an additional receptor binding protein, such as glycoprotein D for herpes simplex virus (HSV) (29) or gp42 for Epstein-Barr virus (11), whereas receptor binding activity lies within gB for cytomegalovirus (CMV) and Kaposi's sarcoma-associated herpesvirus (1, 2). While much progress has been made in understanding how membrane fusion is promoted by single-component fusion proteins, little is known of how multiple components mediate fusion. Although it seems likely that multiple component fusion machines require cooperation among the fusion proteins, it remains unclear if and how herpesvirus glycoproteins interact with one another either du...

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“…Although the immunologic responses against several of the major HCMV surface glycoproteins, including glycoprotein B (gB) and gH, have been extensively characterized, only limited studies of the responses to the gM/gN complex have been reported (13,18,(30)(31)(32)(41)(42)(43). The gM/gN complex is the most abundant glycoprotein component of the HCMV virion envelope (44).…”

mentioning

confidence: 99%

Human Cytomegalovirus Infection Elicits a Glycoprotein M (gM)/gN-Specific Virus-Neutralizing Antibody Response

Shimamura

Mach

Britt

2006

J Virol

105

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Human cytomegalovirus (HCMV) is a ubiquitous human pathogen that infects 40 to 90% of adult human populations. HCMV infections are often asymptomatic in healthy individuals but can cause severe organ and life-threatening disease in immunocompromised patients. The antiviral antibody response to HCMV infection is complex and is known to include virus-neutralizing antibody production against surface glycoproteins encoded by HCMV. We have investigated the human antibody response to a complex of HCMV surface glycoproteins composed of glycoprotein M (gM)/gN, the gene products of the UL100 and UL73 open reading frames. Mouse monoclonal antibodies generated against gM/gN have previously been shown to neutralize HCMV infection of human fibroblasts in vitro. To determine whether human antibodies reactive with the gM/gN complex possess virus-neutralizing properties, we isolated human antibodies reactive with gM/gN from pooled human HCMV hyperimmune globulin by affinity purification using recombinant gM/gN. The affinitypurified human anti-gM/gN antibodies reacted specifically by immunofluorescence with HCMV-infected human fibroblasts and with cells transiently expressing gM/gN, but not with cells transfected with plasmids encoding other immunogenic HCMV proteins. The anti-gM/gN antibodies also reacted specifically only with gM/gN in immunoblot assays using lysates of transfected cells expressing specific HCMV proteins. Last, human anti-gM/gN antibodies efficiently neutralized infectious HCMV in vitro with a capacity comparable to that of human anti-gB antibodies. These data indicated that gM/gN can elicit a virus-neutralizing antibody response in humans infected with HCMV and therefore should be considered a potential candidate for inclusion in prophylactic CMV vaccines.

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Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response

Cited by 105 publications

References 45 publications

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Coiled-Coil Domains in Glycoproteins B and H Are Involved in Human Cytomegalovirus Membrane Fusion

Human Cytomegalovirus Infection Elicits a Glycoprotein M (gM)/gN-Specific Virus-Neutralizing Antibody Response

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