Human Cytomegalovirus Escapes a Naturally Occurring Neutralizing Antibody by Incorporating It into Assembling Virions

Kate M., et al. 2011. Cell Host & Microbe. 10, 197-209, Sep. 15.

Speaker: Yu-Chi Su (蘇育琦)                                        Time: 14:10~15:00, Apr. 25

Commentator: Dr. Shun-hua Chen (陳舜華老師)        Place: Room 601

Abstract:

Human cytomegalovirus (CMV) belongs to the Herpesviridae family that has the ability to remain lifelong latent within healthy adults, but can be life-threatening for immunecompromised individuals. MSL-109 is a human monoclonal IgG isolated from a CMV seropositive patient. It is a naturally occurring neutralizing antibody that specifically recognizes CMV glycoprotein gH complexes. MSL-109 was tested as an adjuvant treatment for HIV patients, but it was halted due to insufficient efficacy in a clinical trail. In order to reveal how CMV escapes from MSL-109 neutralization, the authors generated an MSL-109-resistant CMV strain. They first demonstrated that, MSL-109 binds to gH/gL complexes via interaction with the epitope only exposed on cells but not on virions. During generation of the MSL-109-resistant strain, they showed that the resistance of MSL-109 is not dependent on a permanent genetic mutation and can be reversed rapidly after removing the antibody. The authors further demonstrated that the selective incorporation of antibody to assembling MSL-109 resistant CMV occurs in a dose-dependent manner. The MSL-109-resistant CMV enter naïve cells by low pH-dependant endocytosis and require the Fc domain of MSL-109. This entry pathway is different from that of wild type CMV which occurs at neutral pH. The resistance mechanism may explain the clinical failure of MSL-109 as viral antibody escape. Obviously, it is important to establish the mechanism of CMV escape from antibody neutralization before further development of antibody therapeutics for CMV disease.

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