title: Human cytomegalovirus escapes a naturally occurring neutralizing antibody by incorporating it into assembling virions.
abstract: Human cytomegalovirus (CMV) is a common but difficult to treat infection of immunocompromised patients. MSL-109 is a human monoclonal IgG isolated from a CMV seropositive individual that recognizes the viral glycoprotein H (gH) surface antigen complexes that mediate entry. Although MSL-109 blocks CMV infection in vitro, it lacked sufficient efficacy in human trials, and CMV isolated from treated patients suggested the evolution of MSL-109 resistance. To understand how CMV escapes MSL-109, we characterized a MSL-109-resistant CMV strain. Our results elucidate a nongenetic escape mechanism in which the antibody is selectively taken up by infected cells and incorporated into assembling virions in a dose-dependent manner. The resistant virus then utilizes the Fc domain of the incorporated antibody to infect naive nonimmune cells. This resistance mechanism may explain the clinical failure of MSL-109, illustrate a general mechanism of viral antibody escape, and inform antiviral vaccine and therapeutic development.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Manley
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Joseph
authors.initials: J
authors.lastname: Szustakowski
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.forename: Teresa
authors.initials: T
authors.lastname: Compton
authors.forename: Adam L
authors.initials: AL
authors.lastname: Feire
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D014771:Virion / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019065:Virus Assembly
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral