Human herpesvirus‐6A gQ1 and gQ2 are critical for human CD46 usage

Abstract

Based on genetic and antigenic differences and on their cell tropism, human herpes virus-6 (HHV-6) has been classified into two variants, HHV-6A and HHV-6B. Recently, these variants were re-classified as two different species. The HHV-6A glycoprotein complex, gH/gL/gQ1/gQ2 binds to its cellular receptor, CD46; however, the corresponding complex in HHV-6B rarely binds to CD46. To determine which viral molecules in the glycoprotein complex determine HHV-6A-CD46 binding, each molecule of the HHV-6A complex (i.e., gH, gL, gQ1, or gQ2) was replaced with the corresponding HHV-6B molecule, and the ability of the replaced protein to be incorporated into the complex and the ability of the complex to bind CD46 were examined. It was found that when all four glycoproteins were expressed, they were able to form a tetrameric complex. However, a complex formed by HHV-6A gH/gL/ gQ1/gQ2 complexes replaced with HHV-6B gQ1 or gQ2 scarcely bind CD46, whereas HHV-6A complexes in which gH or gL was replaced with the HHV-6B molecules did bind it. These results indicate that HHV-6A gQ1 and gQ2 play an important role in CD46 binding.Key words CD46 antigen, glycoprotein Q1, glycoprotein Q2, human herpesvirus-6A and -6B.Human herpesvirus 6 (HHV-6) belongs to the betaherpesvirus subfamily (1). It was first isolated from peripheral blood lymphocytes of patients with lymphoproliferative disorders (2). Based on their genetic and antigenic differences and their cell tropism, HHV-6 isolates were classified into two variants, HHV-6A and HHV-6B (2-5). Recently, HHV-6A and HHV-6B were re-classified as different species (see the Virus Taxonomy List 2011; reference (6)). Primary infections with HHV-6B cause exanthem subitum (7). The diseases caused by HHV-6A, if any, are unknown. Although the homology between the HHV-6A and -6B is almost 90% over their entire genome, HHV-6A can infect a greater variety of human cells than HHV-6B (8-11). However, which HHV-6 genes are responsible for the differences between HHV-6A and HHV-6B in cell tropism remains unclear.Human CD46 is a cellular receptor of HHV-6 (12) and its viral ligand is a glycoprotein complex made up of viral gH/gL/gQ1/gQ2 (13). Studies using neutralizing antibodies against HHV-6A/B gQ1 have shown that gQ1 plays an important role in viral entry (14,15). In herpesviruses, formation of the gH/gL heterodimer is critical for viral function (16). In HHV-6A, the gH/gL heterodimer requires the additional association of gQ1 and gQ2 (13) for the trafficking and receptor binding of this complex (17). HHV-6B gH/gL also associates with the gQ1/gQ2 complex (14); however, the HHV-6A gH/ gL/gQ1/gQ2 complex binds to its human cellular receptor, CD46, whereas the corresponding complex in some HHV-6B strains seems not to bind it (8, 13). More recently, we found that human CD134 functions as a specific receptor for HHV-6B, but not for HHV-6A, and † Chyntia Jasirwan, Yoshikazu Furusawa and Huamin Tang contributed equally to this study. List of Abbreviations: a.a., amino acid; CBMC, umbilical cord blood mo...

Detailed Study of the Interaction between Human Herpesvirus 6B Glycoprotein Complex and Its Cellular Receptor, Human CD134

“…Thus, it could be inferred that the gH and gL subunits of HHV-6A and -6B do not contribute to the binding of the tetrameric complexes to different receptors. On the other hand, the gQ1 and gQ2 subunits of HHV-6A and -6B share relatively low sequence identity (21)(22)(23), and we have confirmed that a chimeric complex composed of gQ2, gH, and gL of HHV-6B and gQ1 of HHV-6A could bind CD46, although at a lower affinity (24). Therefore, it is highly likely that the gQ1 subunit is responsible for the differential receptor binding of the gH/gL/gQ1/gQ2 complexes of HHV-6A and -6B.…”

“…We reported previously that the chimeric complex composed of gQ1 and gQ2 of HHV-6A and gH and gL of HHV-6B could bind to CD46 (24). Furthermore, the chimeric complex composed of gQ1 and gQ2 of HHV-6B and gH and gL of HHV-6A could bind to CD134 (13).…”

Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

“…A similar solution may have been adopted in HCMV with gO and ULs binding to gH/gL to form complexes that assume the functions of receptor binding and fusion regulation. Similar to HCMV, it has been shown that in HHV-6A, the gQ1/gQ2 components of the tetrameric gH/gL/gQ1/gQ2 complex are directly involved in binding to the entry receptor CD46 (45).…”

Complement Evasion Strategies of Viruses: An Overview

“…More recently, it has been demonstrated that apart from the heterotetramer complex, gB is also essential for the membrane fusion by HHV-6 (Tanaka et al, 2013). Among the components of the heterotetramer, gQ1 and gQ2 seem to play a critical role in binding to CD46 (Jasirwan et al, 2014).…”