The Combination of gQ1 and gQ2 in Human Herpesvirus 6A and 6B Regulates the Viral Tetramer Function for Their Receptor Recognition.

Human herpesvirus 6A (HHV-6A) and HHV-6B use different cellular receptors, human CD46 and CD134, respectively and have different cell tropisms although they have 90% similarity at the nucleotide level. An important feature that characterizes HHV-6A/6B is the glycoprotein H (gH)/gL/gQ1/gQ2 complex (a tetramer) that each virus has specifically on its envelope. Here, to determine which molecules in the tetramer contribute to the specificity for each receptor, we developed a cell-cell fusion assay system for HHV-6A and HHV-6B that uses the cells expressing CD46 or CD134. With this system, when we replaced the gQ1 or gQ2 of HHV-6A with that of HHV-6B in the tetramer, the cell fusion activity mediated by glycoproteins via CD46 was lower than that done with the original-type tetramer. When we replaced the gQ1 or the gQ2 of HHV-6A with that of HHV-6B in the tetramer, the cell fusion mediated by glycoproteins via CD134 was not seen. In addition, we generated two types of C-terminal truncation mutants of HHV-6A gQ2 (AgQ2) to examine the interaction domains of HHV-6A gQ1 (AgQ1) and AgQ2. We found that amino acid residues 163 to 185 in AgQ2 are important for interaction of AgQ1 and AgQ2. Finally, to investigate whether HHV-6B gQ2 (BgQ2) can complement AgQ2, an HHV-6A genome harboring BgQ2 was constructed. The mutant could not produce an infectious virus, indicating that BgQ2 cannot work for the propagation of HHV-6A. These results suggest that gQ2 supports the tetramer's function, and the combination of gQ1 and gQ2 is critical for virus propagation.