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

Abstract

The 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.

FIG 1

Schematic of the CMV virion. The CMV virion consists of an ∼235-kb double-stranded DNA genome contained within an icosahedral protein capsid. A tegument layer (blue zone) consisting of many phosphoproteins lies between the capsid and the outer membrane. The outer lipid bilayer membrane is studded with multiple glycoprotein complexes.

FIG 2

CMV glycoprotein complexes. The essential CMV glycoprotein complexes required for cell attachment and entry are depicted. The glycoprotein complex (GC) designations are indicated. The pentameric complex (PC) is illustrated on the right and includes the UL128, UL130, and UL131a proteins. Parallel dashed lines represent disulfide linkages between individual envelope proteins.

FIG 3

Model of CMV attachment and entry. (A) CMV entry receptors. (1) CMV initially tethers to cells through interactions between heparan sulfate proteoglycans (HSPGs) and the gB and gM/gN complexes. (2) gB then interacts with cell surface receptors, which may include integrins, epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor alpha (PDGFRα). gH complexes may interact with integrins and additional cell surface receptors. Receptor binding results in signal transduction that likely primes the fusion event. (3) gH/gL complexes and gB then act together to initiate membrane fusion. (B) Cell entry pathways. CMV entry into fibroblast cells occurs at the cell surface and/or in macropinocytic vacuoles and requires gB and the gH/gL/gO complex in a pH-independent fusion event. Entry into epithelial, endothelial, dendritic, and monocytic cells occurs via endocytosis and/or macropinocytosis followed by a pH-dependent fusion event and requires gB, gH/gL/gO, and the PC.

FIG 4

Strategies of CMV envelope protein-mediated immune evasion. (A) Strain polymorphism. Initial CMV infection elicits an antibody response that may not effectively neutralize infection by alternate strains due to variability in the CMV virion envelope proteins. (B) Epitope competition. Antibodies targeting regions of a CMV envelope protein that do not participate in critical attachment or entry processes may sterically block the binding of neutralizing antibodies to critical epitopes. (C) Fc receptor-mediated endocytosis. A CMV virion that is bound by CMV-specific antibodies may cross-link Fc receptors on the cell surface and induce endocytosis of the virion-IgG complex. Viral entry then occurs when the virus fuses with the endosomal membrane within the cell. (D) Glycan shielding. Highly glycosylated surface proteins, such as CMV gB, gO, and gN (Table 1), may prevent antibody binding by limiting access to susceptible epitopes within the glycoprotein or glycoprotein complex. (E) Cell-to-cell fusion. Surface viral envelope proteins may induce fusion between an infected cell and a bystander cell, permitting transfer of infectious material while avoiding exposure to the host neutralizing antibody response.