Abstract
Human herpesvirus 6 (HHV-6) employs the complement regulator CD46 (membrane cofactor protein) as a receptor for fusion and entry into target cells. Like other known herpesviruses, HHV-6 encodes multiple glycoproteins, several of which have been implicated in the entry process. In this report, we present evidence that glycoprotein H (gH) is the viral component responsible for binding to CD46. Antibodies to CD46 co-immunoprecipitated an approximately 110-kDa protein band specifically associated with HHV-6-infected cells. This protein was identified as gH by selective depletion with an anti-gH monoclonal antibody, as well as by immunoblot analysis with a rabbit hyperimmune serum directed against a gH synthetic peptide. In reciprocal experiments, a monoclonal antibody against HHV-6 gH was found to co-immunoprecipitate CD46. Studies using monoclonal antibodies directed against specific CD46 domains, as well as engineered constructs lacking defined CD46 regions, demonstrated a close correspondence between the CD46 domains involved in the interaction with gH and those previously shown to be critical for HHV-6 fusion (i.e. short consensus repeats 2 and 3).
Highlights
Human herpesvirus 6 (HHV-6) employs the complement regulator CD46 as a receptor for fusion and entry into target cells
Studies using monoclonal antibodies directed against specific CD46 domains, as well as engineered constructs lacking defined CD46 regions, demonstrated a close correspondence between the CD46 domains involved in the interaction with glycoprotein H (gH) and those previously shown to be critical for HHV-6 fusion
The cell mixture was lysed and subjected to immunoprecipitation with an anti-human CD46 monoclonal antibodies (mAbs) (J4 – 48); this mAb is specific for the SCR1 domain, which is dispensable for HHV-6 fusion [5, 6]
Summary
Vol 278, No 28, Issue of July 11, pp. 25964 –25969, 2003 Printed in U.S.A. Interaction of Glycoprotein H of Human Herpesvirus 6 with the Cellular Receptor CD46*. The best studied members of the herpesvirus family enter cells by direct fusion with the plasma membrane in a process involving binding of viral glycoproteins to specific protein receptors on the target cell (reviewed in Ref. 2). We identified CD46 (membrane cofactor protein) as a cellular receptor mediating fusion and entry for both HHV-6 variants [3] This glycoprotein serves as a cellular receptor mediating critical events in the infectious process of other human pathogens, including binding/fusion/ entry of measles virus, pilus binding of different pathogenic Neisseriae, and adhesion of group A Streptococci (reviewed in Ref. 4). GB (the most highly conserved glycoprotein among herpesviruses) and another glycoprotein, gp82-gp105, ( far found only in HHV-6 and the related -herpesvirus, HHV-7) appear to be critical for the fusion/entry process, as specific antibodies against these proteins block both virus infectivity and syncytia. Mapping studies demonstrated that the CD46 determinants critical for gH binding reside in SCR2 and SCR3, consistent with our previous study [5] indicating the importance of the same CD46 domains for HHV-6 fusion
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