Identification of the Human Herpesvirus 6A gQ1 Domain Essential for Its Functional Conformation

Maeki, Takahiro; Hayashi, Mayuko; Kawabata, Akiko; Tang, Huiping; Yamanishi, Koichi; Mori, Yasuko

doi:10.1128/jvi.00611-13

Cited by 9 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we reported that amino acid residues 494 to 497 of HHV-6A gQ1 and 484 to 496 of HHV-6B gQ1 are important for the function of gQ1 proteins (11,19). Here, we found that an E127Q mutation in HHV-6B gQ1 could completely abolish its function.…”

Section: Discussionsupporting

confidence: 51%

“…6B). As mentioned previously, the HHV-6B gH/gL/ gQ1/gQ2 complex did not bind to CD46 (12), even when HHV-6B gQ1 formed a complex with HHV-6A gH, gL, and gQ2 (19) (Fig. 6C).…”

Section: Fig 3 Soluble Cd134 Blocks Hhv-6b Infection Soluble Cd134 Pmentioning

confidence: 71%

“…Much is known about the receptor-ligand binding of HHV-6A. Short consensus repeats 2 and 3 (SCR2 and -3) of CD46 are required for its binding to the HHV-6A gH/gL/ gQ1/gQ2 complex (17,18), and complex formation is required for CD46 binding to its viral ligand (19,20). However, no such analysis of the binding of HHV-6B ligand to CD134 had been performed.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Tang

Wang

Mahmoud

et al. 2014

J Virol

Self Cite

View full text Add to dashboard Cite

Recently, we identified a novel receptor, CD134, which interacts with the human herpesvirus 6B (HHV-6B) glycoprotein (g)H/ gL/gQ1/gQ2 complex and plays a key role in the entry of HHV-6B into target cells. However, details of the interaction between the HHV-6B gH/gL/gQ1/gQ2 complex and CD134 were unknown. In this study, we identified a cysteine-rich domain (CRD), CDR2, of CD134 that is critical for binding to the HHV-6B glycoprotein complex and HHV-6B infection. Furthermore, we found that the expression of HHV-6B gQ1 and gQ2 subunits was sufficient for CD134 binding, which is different from the binding of human herpesvirus 6A (HHV-6A) to its receptor, CD46. Finally, we identified a region in gQ1 critical for HHV-6B gQ1 function. These results contribute much to our understanding of the interaction between this ligand and receptor. IMPORTANCEWe identified the domain in HHV-6B entry receptor CD134 and the components in the HHV-6B gH/gL/gQ1/gQ2 complex required for ligand-receptor binding during HHV-6B infection. Furthermore, we identified domains in gQ1 proteins of HHV-6A and -6B and a key amino acid residue in HHV-6B gQ1 required for its function. These data should be the basis for further investigation of ligand-receptor interaction in the study of HHV-6A and -6B. Shortly after its discovery, human herpesvirus 6 (HHV-6) was recognized as a single virus species comprised of two variants, HHV-6A and HHV-6B (1-4). Recently, HHV-6 variants have been reclassified as two virus species based on the different biocharacteristics of these two viruses with respect to the fields of biology, immunology, and epidemiology, and so on (5).One striking difference between HHV-6A and HHV-6B is their cell tropism. HHV-6A infects a wider range of cells than HHV-6B (5-7). Although determinants of viral cell tropism lie in each step of the virus life cycle in target cells, the differences in receptor preference of HHV-6A and -6B may contribute much to their cell tropism. Human CD46 was identified as the cell receptor for HHV-6 (8) and binds the HHV-6A gH/gL/gQ1/gQ2 complex (9, 10). Interestingly, we found that a similar glycoprotein complex exists in HHV-6B but does not bind to CD46 (11, 12), even though it shares a relatively high sequence identity with the glycoprotein in HHV-6A (especially the gH and gL components). Recently, we found that human CD134 is a specific cellular receptor for HHV-6B and binds to the HHV-6B gH/gL/gQ1/gQ2 complex (13). While CD46 is expressed on all nucleated cells (14, 15), CD134 is expressed mainly on activated T cells (16). The different expression profiles of these two cellular receptors may be one of the key determinants of the differences in cell tropism of HHV-6A and -6B. However, it is still unknown how these two similar viral ligands bind to different cellular receptors.Analysis of the receptor-ligand binding process would contribute not only to our understanding of the viral life cycle itself but also to the development of treatment methods to block the virus life cycle at the first step. M...

show abstract

Section: Discussionsupporting

confidence: 51%

“…6B). As mentioned previously, the HHV-6B gH/gL/ gQ1/gQ2 complex did not bind to CD46 (12), even when HHV-6B gQ1 formed a complex with HHV-6A gH, gL, and gQ2 (19) (Fig. 6C).…”

Section: Fig 3 Soluble Cd134 Blocks Hhv-6b Infection Soluble Cd134 Pmentioning

confidence: 71%

See 1 more Smart Citation

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

Tang

Wang

Mahmoud

et al. 2014

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Receptors are targets for neutralization [24] and can be used to create receptor-transgenic animal models that support infection [25]. The essential components for membrane fusion by HHV-6A and HHV-6B are gB and the gH/gL/gQ1/gQ2 complex [26-28]. gQ2 and gM are essential for virus production of HHV-6A since virus stocks could not be generated from BACs with disruptions in these ORFs [28,29].…”

Section: Productive Replicationmentioning

confidence: 99%

Roseolovirus molecular biology: recent advances

Krug

Pellett

2014

Current Opinion in Virology

View full text Add to dashboard Cite

Human herpesviruses 6A, −6B, and −7 (HHV-6A, −6B, and −7) are classified within the roseolovirus genus of the betaherpesvrus subfamily. Most humans likely harbor at least two of these large DNA viruses, and 1% of humans harbor germline chromosomally integrated HHV-6A or HHV-6B genomes. Differences at the genetic level manifest as distinct biologic properties during infection and disease. We provide a brief synopsis of roseolovirus replication and highlight the unique properties of their lifecycle and what is known about the viral gene products that mediate these functions. In the nearly 30 years since their discovery, we have only begun to unlock the molecular strategies these highly evolved pathogens employ to establish and maintain chronic infections in humans.

show abstract

“…MAb 87-y-13 does not neutralize rHHV-6A BACgB(N347K) or rHHV-6A BACgB(N347A) infection. We reported previously that the MAb against HHV-6A gQ1 (AgQ1-1) has high neutralizing activity for HHV-6A but not for HHV-6B (25) and that the MAb against HHV-6B gQ1 (KH-1) has high neutralizing activity for HHV-6B but not for HHV-6A (26). Here we tested whether MAb 87-y-13 would block infection by rHHV-6A BACgB(N347K) or rHHV-6A BACgB(N347A), and we compared the action of MAb 87-y-13 with the neutralizing activities of Mabs AgQ1-1 and KH-1.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Identification of the Human Herpesvirus 6A gQ1 Domain Essential for Its Functional Conformation

Cited by 9 publications

References 39 publications

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

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

Roseolovirus molecular biology: recent advances

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

Contact Info

Product

Resources

About