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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]