Formation of the glycoprotein gH/gL heterooligomer has important implications for understanding the pathology of HHV-6-associated disease because this complex is essential for infectivity and fusogenic cell-to-cell spread (Josephs et al., 1991; Liu et al., 1993a,b; Qian et al., 1993; Anderson et al., 1996; Takeda et al., 1997; Anderson and Gompels, 1999). Definition of the HHV-6 gH domain involved in protein-protein interactions is addressed by targeting regions defined by conserved cysteines identified by alignment of gH amino acid sequences representative of all herpesvirus subfamilies. The N-terminus of HHV-6 gH includes a 230-amino-acid domain required for interaction with HHV-6 gL encompassing residues conserved specifically among betaherpesviruses. HCMV homologues, UL75 (gH) or UL115 (gL), can substitute for HHV-6 glycoproteins and participate in heterologous complex formation (Anderson et al., 1996). Furthermore, the region that governs this heterologous gL binding also maps to the N-terminal portion of HHV-6 gH. Surprisingly, further deletion of HHV-6 gH to 145-amino acid-domain residues abolishes complex formation with HHV-6 gL, but allows interaction with HCMV gL (Anderson et al., 1996). Anti-fusion monoclonal antibodies specific for HHV-6 gH inhibits infection and prevent cellular spread by syncytia formation (Foa-Tomasi et al., 1991). Reactivity of these monoclonal antibodies with gH deletion mutants suggests a conserved C-terminal fusion-associated domain (Anderson and Gompels, 1999).
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