Human herpesvirus-6 (HHV-6) is a T lymphotropic herpesvirus belonging to the Betaherpesvirinae subfamily. HHV-6 was long classified into variants A and B (HHV-6A and HHV-6B); however, recently, HHV-6A and HHV-6B were reclassified as different species. The process of herpesvirus entry into target cells is complicated, and in the case of HHV-6A and HHV-6B, the detailed mechanism remains to be elucidated, although both viruses are known to enter cells via endocytosis. In this paper, (1) findings about the cellular receptor and its ligand for HHV-6A and HHV-6B are summarized, and (2) a schematic model of HHV-6A’s replication cycle, including its entry, is presented. In addition, (3) reports showing the importance of lipids in both the HHV-6A envelope and target-cell membrane for viral entry are reviewed, and (4) glycoproteins involved in cell fusion are discussed. 1. Introduction The herpesviridae are a family of double-stranded enveloped DNA viruses. Their entry into host cells proceeds as follows. First, the virus binds to its target cell through a specific receptor. Second, herpesviruses enter cells via two different pathways: (a) direct fusion of the viral envelope with the target-cell plasma membrane or (b) endocytosis followed by fusion between the viral and cellular membranes in the endosomal compartment [1]. Human herpesvirus-6 (HHV-6) was initially isolated from the peripheral blood of patients with lymphoproliferative disorders, in 1986 [2]. It belongs to the Betaherpesvirinae subfamily, along with human cytomegalovirus (HCMV) and Human herpesvirus-7 (HHV-7), and is a member of the genus Roseolovirus, along with HHV-7. HHV-6 was originally classified into variants A and B (HHV-6A and HHV-6B), based on differences in genetic, antigenic, and growth characteristics [3–5]. However, recently, HHV-6A and HHV-6B were reclassified into different species (Virus Taxonomy List 2011). The homology of entire genome sequence between both is nearly 90% [6–8]. Primary infection of HHV-6B causes exanthem subitum [9], and HHV-6A has been reported to be involved in several diseases, including encephalitis [10], hepatitis [11], glioma [12], and multiple sclerosis [13]. However, the detailed replication cycle of HHV-6A and HHV-6B after entering the cell remains to be elucidated. For some of the steps, different groups have reported conflicting results. Regarding the ligand and receptor for HHV-6A and HHV-6B, Santoro et al. reported that the cellular receptor for both viruses is CD46 [14]. Our group showed that the glycoprotein gH/gL/gQ1/gQ2 complex [15] is the ligand
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