Abstract
We employed a quantitative cell fusion assay to identify structural domains of CD46 required for its function as a receptor for human herpesvirus 6 (HHV-6). We examined the activities of recombinant variants of CD46, including different isoforms as well as engineered truncations and molecular chimeras with decay-accelerating factor, a related protein in the family of regulators of complement activation (RCA). We observed strong receptor activity for all four CD46 isoforms, which differ in the membrane-proximal extracellular and cytoplasmic domains, indicating that the critical determinants for HHV-6 receptor activity reside outside the C-terminal portion of CD46. Analysis of the short consensus repeat (SCR) regions that comprise most of the extracellular portion of CD46 indicated a strong dependence on SCRs 2 and 3 and no requirement for SCRs 1 or 4. Fusion-inhibition studies with SCR-specific monoclonal antibodies supported the essential role of SCRs 2 and 3 in HHV-6 receptor activity. These findings contrast markedly with fusion mediated by measles virus glycoproteins for which we observed a strict dependence on SCRs 1 and 2, consistent with previous reports. These results expand the emerging notion that CD46 and other members of the RCA family are co-opted in distinct manners by different infectious pathogens.
Highlights
Human herpesvirus 6 (HHV-6)1 is a recently discovered member of the -herpesvirus subfamily, for which two major subgroups (A and B) have been identified
Consistent with the results obtained with the genetic constructs, we observed that HHV-6 fusion with target cells expressing endogenous CD46 was inhibited by monoclonal antibodies (mAbs) M177, which is directed against SCR2 [15, 18], as well as by mAb M160 directed against SCR3 [15]; by contrast, mAb GB24 against SCR4 [35, 36] did not inhibit HHV-6 fusion; enhancement was consistently noted
The results presented demonstrate that short consensus repeats (SCRs) domains 2 and 3 of CD46 are required for HHV-6 receptor activity; this differs markedly from the requirement of SCRs 1 and 2 for measles virus (MV)
Summary
Vol 277, No 42, Issue of October 18, pp. 39112–39118, 2002 Printed in U.S.A. Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function*. Fusion-inhibition studies with SCR-specific monoclonal antibodies supported the essential role of SCRs 2 and 3 in HHV-6 receptor activity These findings contrast markedly with fusion mediated by measles virus glycoproteins for which we observed a strict dependence on SCRs 1 and 2, consistent with previous reports. These results expand the emerging notion that CD46 and other members of the RCA family are co-opted in distinct manners by different infectious pathogens. Subsequent studies focused on identifying critical domains of CD46 required for MV receptor function, using functional assays of viral infectivity and/or cell fusion as well as binding assays of MV virions or hemagglutinin (HA) [13,14,15,16,17,18,19,20]. Our results highlight major differences in the CD46 determinants necessary for HHV-6 versus MV receptor activity
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