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
]. 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
]. 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 for HHV-6A [16
], and that its receptor is CD46 [17
]. However, in the case of HHV-6B (strain HST, an isolate from an infant with exanthem subitum), we reported that, of two complexes found in this virus, gH/gL/gQ and gH/gL/gO neither binds to CD46 [19
]. This discrepancy might be due to the difference in HHV-6B strain (Santoro et al. used strains Z29 and PL1, while we used HST) or some other reason.
In this paper, (1) previous reports about the cellular receptor and its ligand for HHV-6A and HHV-6B are summarized, and (2) findings about the entry of HHV-6A and HHV-6B into host cells are reviewed, and a schematic model of HHV-6A's replication cycle 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. Finally, (4) glycoproteins that have been shown to play a critical role in cell fusion (glycoprotein H, glycoprotein B) are discussed briefly.