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

Abstract

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.

Functional screening for anti-CMV biologics identifies a broadly neutralizing epitope of an essential envelope protein

“…The coevolution of CMV with its human host over millions of years has enabled it to evade immune clearance4950. Besides well-characterized strategies to evade T cell and NK cell activation, CMV may limit the generation of neutralizing antibodies to essential domains of its envelope50.…”

“…Besides well-characterized strategies to evade T cell and NK cell activation, CMV may limit the generation of neutralizing antibodies to essential domains of its envelope50. Thus, generating antibodies in mice immunized with purified virions will allow for the identification of neutralizing mAbs targeting functionally critical regions of envelope proteins that are obscured in the human host.…”

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

“…Human cytomegalovirus (HCMV), also known as human herpesvirus 5, is a widespread pathogen among human populations [1][2][3]. To establish a successful infection, HCMV depends on a unique set of immune evasion strategies, using encoded proteins and mRNA to avoid a competent innate and adaptive immune response [4]. HCMV-mediated infections are a recognized cause of morbidity and mortality in immunocompromised individuals as compared to otherwise healthy or immunocompetent individuals [5][6][7].…”

Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

“…However, our understanding of anti-HCMV humoral immunity is complicated by the number of distinct glycoprotein complexes that contain neutralizing epitopes, most notably glycoprotein B (gB; fusion protein) and the pentameric complex gH/gL/UL128-131A (PC; necessary for entry into epithelial/endothelial cells) (19). While all vaccine platforms tested thus far ultimately failed Human cytomegalovirus (HCMV) is the most common congenital infection and a known cause of microcephaly, sensorineural hearing loss, and cognitive impairment among newborns worldwide.…”