Cytoplasmic tail domain of glycoprotein B is essential for HHV-6 infection

Mahmoud, Nora F.; Jasirwan, Chyntia Olivia Maurine; Kanemoto, Satoshi; Wakata, Aika; Wang, Bochao; Hata, Yoshiya; Nagamata, Satoshi; Kawabata, Akiko; Tang, Huiping; Mori, Yasuko

doi:10.1016/j.virol.2015.12.018

Cited by 4 publications

(2 citation statements)

References 48 publications

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“…However, coexpression of gH, gL, gQ1, and gQ2 with gB could not induce cell-cell fusion in the cells. Recently, we reported that gB was located in the trans-Golgi network (TGN) when HHV-6A gB was transfected into the cells (22). Therefore, we thought that because HHV-6A gB was incapable of cell surface expression, gH, gL gQ1, and gQ2 could not work together with gB on the cell membrane to induce cell-cell fusion.…”

Section: Resultsmentioning

confidence: 99%

The Neutralizing Linear Epitope of Human Herpesvirus 6A Glycoprotein B Does Not Affect Virus Infectivity

Wakata

Kanemoto

Tang

et al. 2018

J Virol

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Human herpesvirus 6A (HHV-6A) glycoprotein B (gB) is a glycoprotein consisting of 830 amino acids and is essential for the growth of the virus. Previously, we reported that a neutralizing monoclonal antibody (MAb) called 87-y-13 specifically reacts with HHV-6A gB, and we identified its epitope residue at asparagine (Asn) 347 on gB. In this study, we examined whether the epitope recognized by the neutralizing MAb is essential for HHV-6A infection. We constructed HHV-6A bacterial artificial chromosome (BAC) genomes harboring substitutions at Asn347, namely, HHV-6A BACgB(N347K) and HHV-6A BACgB(N347A). These mutant viruses could be reconstituted and propagated in the same manner as the wild type and their revertants, and MAb 87-y-13 could not inhibit infection by either mutant. In a cell-cell fusion assay, Asn at position 347 on gB was found to be nonessential for cell-cell fusion. In addition, in building an HHV-6A gB homology model, we found that the epitope of the neutralizing MAb is located on domain II of gB and is accessible to solvents. These results indicate that Asn at position 347, the linear epitope of the neutralizing MAb, does not affect HHV-6A infectivity. Glycoprotein B (gB) is one of the most conserved glycoproteins among all herpesviruses and is a key factor for virus entry. Therefore, antibodies targeted to gB may neutralize virus entry. Human herpesvirus 6A (HHV-6A) encodes gB, which is translated to a protein of about 830 amino acids (aa). Using a monoclonal antibody (MAb) for HHV-6A gB, which has a neutralizing linear epitope, we analyzed the role of its epitope residue, N347, in HHV-6A infectivity. Interestingly, this gB linear epitope residue, N347, was not essential for HHV-6A growth. By constructing a homology model of HHV-6A gB, we found that N347 was located in the region corresponding to domain II. Therefore, with regard to its neutralizing activity against HHV-6A infection, the epitope on gB might be exposed to solvents, suggesting that it might be a target of the immune system.

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Section: Resultsmentioning

confidence: 99%

The Neutralizing Linear Epitope of Human Herpesvirus 6A Glycoprotein B Does Not Affect Virus Infectivity

Wakata

Kanemoto

Tang

et al. 2018

J Virol

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“…Antibodies. The following mouse monoclonal antibodies (Mabs) have been described: Mabs for HHV-6A gH (gH1-1) (26), gL (AgL3), gH/gL complex (gHgL A2) (26), gQ1 (i.e., gQ1-119 [40], AgQ 1-1 [35], and gQ1-1 [27]), gQ2 (gQ24-2) (26), and hCD46 (M177 [41] and J4.48 [16,23]) and hCD134 (28). Rabbit polyclonal antibody specific for HHV-6A U11 was reported (33).…”

Section: Methodsmentioning

confidence: 99%

The Combination of gQ1 and gQ2 in Human Herpesvirus 6A and 6B Regulates the Viral Tetramer Function for Their Receptor Recognition

Wakata

Tjan

Nishimura

et al. 2021

J Virol

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Human herpesvirus 6A (HHV-6A) and HHV-6B use different cellular receptors, human CD46 and CD134, respectively and have different cell tropisms although they have 90% similarity at the nucleotide level. An important feature that characterizes HHV-6A/6B is the glycoprotein H (gH)/gL/gQ1/gQ2 complex (a tetramer) that each virus has specifically on its envelope. Here, to determine which molecules in the tetramer contribute to the specificity for each receptor, we developed a cell-cell fusion assay system for HHV-6A and HHV-6B that uses the cells expressing CD46 or CD134. With this system, when we replaced the gQ1 or gQ2 of HHV-6A with that of HHV-6B in the tetramer, the cell fusion activity mediated by glycoproteins via CD46 was lower than that done with the original-type tetramer. When we replaced the gQ1 or the gQ2 of HHV-6A with that of HHV-6B in the tetramer, the cell fusion mediated by glycoproteins via CD134 was not seen. In addition, we generated two types of C-terminal truncation mutants of HHV-6A gQ2 (AgQ2) to examine the interaction domains of HHV-6A gQ1 (AgQ1) and AgQ2. We found that amino acid residues 163 to 185 in AgQ2 are important for interaction of AgQ1 and AgQ2. Finally, to investigate whether HHV-6B gQ2 (BgQ2) can complement AgQ2, an HHV-6A genome harboring BgQ2 was constructed. The mutant could not produce an infectious virus, indicating that BgQ2 cannot work for the propagation of HHV-6A. These results suggest that gQ2 supports the tetramer's function, and the combination of gQ1 and gQ2 is critical for virus propagation. IMPORTANCE Glycoprotein Q2 (gQ2), an essential gene for virus propagation, forms a heterodimer with gQ1. The gQ1/gQ2 complex has a critical role in receptor recognition in the gH/gL/gQ1/gQ2 complex (a tetramer). We investigated whether gQ2 regulates the specific interaction between the HHV-6A or -6B tetramer and CD46 or CD134. We established a cell-cell fusion assay system for HHV-6A/6B and switched the gQ1 or gQ2 of HHV-6A with that of HHV-6B in the tetramer. Although cell fusion was induced via CD46 when gQ1 or gQ2 was switched between HHV-6A and -6B, the activity was lower than that of the original combination. When gQ1 or gQ2 was switched in HHV-6A and -6B, no cell fusion was observed via CD134. HHV-6B gQ2 could not complement the function of HHV-6A's gQ2 in HHV-6A propagation, suggesting that the combination of gQ1 and gQ2 is critical to regulate the specificity of the tetramer's function for virus entry.

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Glycoproteins of HHV-6A and HHV-6B

Tang

Mori

2018

Advances in Experimental Medicine and Biology

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Recently, human herpesvirus 6A and 6B (HHV-6A and HHV-6B) were classified into distinct species. Although these two viruses share many similarities, cell tropism is one of their striking differences, which is partially because of the difference in their entry machinery. Many glycoproteins of HHV-6A/B have been identified and analyzed in detail, especially in their functions during entry process into host cells. Some of these glycoproteins were unique to HHV-6A/B. The cellular factors associated with these viral glycoproteins (or glycoprotein complex) were also identified in recent years. Detailed interaction analyses were also conducted, which could partially prove the difference of entry machinery in these two viruses. Although there are still issues that should be addressed, all the knowledges that have been earned in recent years could not only help us to understand these viruses' entry mechanism well but also would contribute to the development of the therapy and/or prophylaxis methods for HHV-6A/B-associated diseases.

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Cytoplasmic tail domain of glycoprotein B is essential for HHV-6 infection

Cited by 4 publications

References 48 publications

The Neutralizing Linear Epitope of Human Herpesvirus 6A Glycoprotein B Does Not Affect Virus Infectivity

The Neutralizing Linear Epitope of Human Herpesvirus 6A Glycoprotein B Does Not Affect Virus Infectivity

The Combination of gQ1 and gQ2 in Human Herpesvirus 6A and 6B Regulates the Viral Tetramer Function for Their Receptor Recognition

Glycoproteins of HHV-6A and HHV-6B

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