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Human herpesvirus 6 is a T lymphotropic herpesvirus, long classified into variants A and B (HHV-6A and HHV-6B) based on differences in sequence and pathogenicity. Recently, however, HHV-6A and HHV-6B were reclassified as different species. Here, we isolated a neutralizing monoclonal antibody (Mab) named AgQ 1-1 that was specific for HHV-6A glycoprotein Q1 (AgQl), and we showed that amino acid residues 494 to 497 of AgQl were critical for its recognition by this Mab. This region was also essential for AgQl's complex formation with gH, gL, and gQ2, which might be important for viral binding to the cellular receptor, CD46. In addition, amino acid residues 494 to 497 are essential for viral replication. Interestingly, this sequence corresponds to the domain on HHV-6B gQl that is critical for recognition by an HHV-6B-specific neutralizing Mab. Within this domain, only Q at position 496 of HHV-6A is distinct from the HHV-6B sequence; however, the mutant AgQl (Q496E) was still clearly recognized by the Mab AgQ 1 -1. Surprisingly, replacement of the adjacent amino acid, in mutant AgQ 1 (C495A), resulted in poor recognition by Mab AgQ 1-1, and AgQl(C495A) could not form the gH/gL/gQl/gQ2 complex. Furthermore, the binding ability of mutant AgQl (L494A) with CD46 decreased, although it could form the gH/gL/gQl/gQ2 complex and it showed clear reactivity to Mab AgQ 1 -1. These data indicated that amino acid residues 494 to 497 of AgQl were critical for the recognition by Mab AgQ 1-1 and essential for AgQl's functional conformation. [ABSTRACT FROM AUTHOR]

Human herpesvirus 6 (HHV-6) is a T cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6A and HHV-6B, based on differences in their genetic, antigenic, and growth characteristics and cell tropisms. The function of HHV-6B should be analyzed more in its life cycle, as more than 90% of people have the antibodies for HHV-6B but not HHV-6A. It has been shown that the cellular receptor for HHV-6A is human CD46 and that the viral ligand for CD46 is the envelope glycoprotein complex gH/gL/gQ1/gQ2; however, the receptor-ligand pair used by HHV-6B is still unknown. In this study, to identify the glycoprotein(s) important for HHV-6B entry, we generated monoclonal antibodies (MAbs) that inhibit infection by HHV-6B. Most of these MAbs were found to recognize gQ1, indicating that HHV-6B gQ1 is critical for virus entry. Interestingly, the recognition of gQ1 by the neutralizing MAb was enhanced by coexpression with gQ2. Moreover, gQ1 deletion or point mutants that are not recognized by the MAb could nonetheless associate with gQ2, indicating that although the MAb recognized the conformational epitope of gQ1 exposed by the gQ2 interaction, this epitope was not related to the gQ2 binding domain. Our study shows that HHV-6B gQ1 is likely a ligand for the HHV- 6B receptor, and the recognition site for this MAb will be a promising target for antiviral agents. [ABSTRACT FROM AUTHOR]