The Human Herpesvirus 6 U100 Gene Product Is the Third Component of the gH-gL Glycoprotein Complex on the Viral Envelope

Mori, Yasuko; Akkapaiboon, Pilailuk; Yang, Xuwei; Yamanishi, Koichi

doi:10.1128/jvi.77.4.2452-2458.2003

Cited by 58 publications

(47 citation statements)

References 46 publications

(41 reference statements)

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“…However, our findings must be considered in terms of the well known association of HHV-6 gH with gL (9, 12-16) and the recent demonstration that these glycoproteins form a trimolecular complex with gp82-gp105, in particular with a minor 80-kDa species representing the mature form with complex N-linked oligosaccharides (20). Moreover, subsequent binding studies with a soluble CD46 construct suggested that the receptor associates with the gH/gL/gp82-gp105 trimolecular complex (43).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, gB (the most highly conserved glycoprotein among herpesviruses) and another glycoprotein, gp82-gp105, (thus far found only in HHV-6 and the related ␤-herpesvirus, HHV-7) appear to be critical for the fusion/entry process, as specific antibodies against these proteins block both virus infectivity and syncytia formation (17)(18)(19). Recently the gp82-gp105 glycoprotein has been shown to be associated with gH-gL complexes in infected cells and virions, and the designation gQ was proposed (20). At present, the precise roles of individual HHV-6 glycoproteins and their possible interplay in the infection process remain poorly understood.…”

Section: Human Herpesvirus 6 (Hhv-6)mentioning

confidence: 99%

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Interaction of Glycoprotein H of Human Herpesvirus 6 with the Cellular Receptor CD46

Santoro

Greenstone

Insinga³

et al. 2003

Journal of Biological Chemistry

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Human herpesvirus 6 (HHV-6) employs the complement regulator CD46 (membrane cofactor protein) as a receptor for fusion and entry into target cells. Like other known herpesviruses, HHV-6 encodes multiple glycoproteins, several of which have been implicated in the entry process. In this report, we present evidence that glycoprotein H (gH) is the viral component responsible for binding to CD46. Antibodies to CD46 co-immunoprecipitated an ϳ110-kDa protein band specifically associated with HHV-6-infected cells. This protein was identified as gH by selective depletion with an anti-gH monoclonal antibody, as well as by immunoblot analysis with a rabbit hyperimmune serum directed against a gH synthetic peptide. In reciprocal experiments, a monoclonal antibody against HHV-6 gH was found to co-immunoprecipitate CD46. Studies using monoclonal antibodies directed against specific CD46 domains, as well as engineered constructs lacking defined CD46 regions, demonstrated a close correspondence between the CD46 domains involved in the interaction with gH and those previously shown to be critical for HHV-6 fusion (i.e. short consensus repeats 2 and 3).Human herpesvirus 6 (HHV-6) 1 is a member of the ␤-herpesvirus subfamily (reviewed in Ref. 1). Two major HHV-6 variants, A and B, have been defined that form two segregated clusters with unique genetic, biologic, and immunologic characteristics. Primary infection with HHV-6 B occurs almost universally in early childhood and has been etiologically linked to exanthema subitum. In adult life, HHV-6 infection and/or reactivation have been associated with a wide range of diseases, including multiple sclerosis, but most of these associations have yet to be substantiated by rigorous epidemiological studies. In immunocompromised people, including those infected with human immunodeficiency virus, HHV-6 B has been implicated as an opportunistic agent that may cause life-threatening respiratory tract and central nervous system infections, as well as bone marrow or organ graft failure. Moreover, HHV-6 may act as a cofactor to accelerate progression of human immunodeficiency virus disease.The best studied members of the herpesvirus family enter cells by direct fusion with the plasma membrane in a process involving binding of viral glycoproteins to specific protein receptors on the target cell (reviewed in Ref.2). Fusion is also facilitated by virus interactions with cell surface glycosaminoglycans. Recently, we identified CD46 (membrane cofactor protein) as a cellular receptor mediating fusion and entry for both HHV-6 variants (3). This glycoprotein also serves as a cellular receptor mediating critical events in the infectious process of other human pathogens, including binding/fusion/ entry of measles virus, pilus binding of different pathogenic Neisseriae, and adhesion of group A Streptococci (reviewed in Ref. 4). CD46 is a member of the regulators of complement activation (RCA) protein family. It is a type I transmembrane glycoprotein of 45-67 kDa, expressed on most or all human nucleated ce...

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Section: Discussionmentioning

confidence: 99%

Section: Human Herpesvirus 6 (Hhv-6)mentioning

confidence: 99%

Interaction of Glycoprotein H of Human Herpesvirus 6 with the Cellular Receptor CD46

Santoro

Greenstone

Insinga³

et al. 2003

Journal of Biological Chemistry

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“…Recently, gH-gL complexes of two betaherpesviruses, HCMV and human herpesvirus 6 (HHV-6), were found to also associate with a third viral glycoprotein, gO or gQ, respectively (7,19); these arrangements mirror the EBV gH-gL-gp42 interactions. Comparison of the sequences for EBV gp42 with those for gO and gQ does not reveal any obvious similarities.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus gp42 Is Posttranslationally Modified To Produce Soluble gp42 That Mediates HLA Class II Immune Evasion

Ressing¹,

Leeuwen²,

Verreck

et al. 2005

J Virol

100

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Epstein-Barr virus (EBV) resides as a persistent infection in human leukocyte antigen (HLA) class II؉ B lymphocytes and is associated with a number of malignancies. The EBV lytic-phase protein gp42 serves at least two functions: gp42 acts as the coreceptor for viral entry into B cells and hampers T-cell recognition via HLA class II molecules through steric hindrance of T-cell receptor-class II-peptide interactions. Here, we show that gp42 associates with class II molecules at their various stages of maturation, including immature ␣␤Ii heterotrimers and mature ␣␤-peptide complexes. When analyzing the biosynthesis and maturation of gp42 in cells stably expressing the viral protein, we found that gp42 occurs in two forms: a full-length type II membrane protein and a truncated soluble form. Soluble gp42 is generated by proteolytic cleavage in the endoplasmic reticulum and is secreted. Soluble gp42 is sufficient to inhibit HLA class II-restricted antigen presentation to T cells. In an almost pure population of Burkitt's lymphoma cells in the EBV lytic cycle, both transmembrane and soluble forms of gp42 are detected. These results imply that soluble gp42 is generated during EBV lytic infection and could contribute to undetected virus production by mediating evasion from T-cell immunity. Epstein-Barr virus (EBV)is a large DNA virus belonging to the family Herpesviridae, subfamily Gammaherpesviriniae, genus Lymphocryptovirus. Like other herpesviruses, EBV persists for life, establishing a latent infection in B lymphocytes with occasional viral reactivation (29). Approximately 90% of the adult population carries EBV DNA. EBV is the causative agent of infectious mononucleosis and is associated with malignancies that originate from lymphoid cells (e.g., Burkitt's lymphoma and Hodgkin's lymphoma) and epithelial cells (e.g., nasopharyngeal carcinoma). In immunosuppressed or immunocompromised individuals, EBV can cause (fatal) lymphoproliferative disease. In contrast, in healthy individuals, EBV is well controlled by the immune system. The widespread and mostly asymptomatic persistent EBV infections in adults reflect the balance between viral replication and host immune control.EBV dedicates part of its genome to immune evasion functions (15). Modulation of T-cell recognition is an important target for EBV, as the virus resides intracellularly for most of its life cycle. Fragments of viral proteins can be displayed at the cell surface by human leukocyte antigen (HLA) class I and class II molecules for the activation of T cells carrying receptors of the appropriate specificity. Activated T cells may then lead to elimination of the pathogen, among other ways through destruction of the infeced cell. To escape from antiviral immunity, EBV should interfere with both CD8 ϩ and CD4 ϩ T-cell responses, particularly as the virus infects B lymphocytes expressing both classes of HLA molecules. The EBV nuclear protein EBNA1 contains a glycine-alanine repeat domain that renders the protein resistant to proteasomal degradation and inhibits...

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“…Hybridoma clones producing MAbs were established from the splenocytes of mice immunized with a purified recombinant protein or UVinactivated HHV-6 virions as described previously (11). MAbs recognizing gQ1 were established as described previously (3,25). The MAb designated BgQ1-202 was raised against recombinant protein BgQ1-N. BgQ1-N was created by the following procedure.…”

Section: Methodsmentioning

confidence: 99%

Analysis of a Neutralizing Antibody for Human Herpesvirus 6B Reveals a Role for Glycoprotein Q1 in Viral Entry

Kawabata

Oyaizu

Maeki

et al. 2011

J Virol

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Human herpesvirus 6 (HHV-6) is a T cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6A and HHV-6B, based on differences in their genetic, antigenic, and growth characteristics and cell tropisms. The function of HHV-6B should be analyzed more in its life cycle, as more than 90% of people have the antibodies for HHV-6B but not HHV-6A. It has been shown that the cellular receptor for HHV-6A is human CD46 and that the viral ligand for CD46 is the envelope glycoprotein complex gH/gL/gQ1/gQ2; however, the receptor-ligand pair used by HHV-6B is still unknown. In this study, to identify the glycoprotein(s) important for HHV-6B entry, we generated monoclonal antibodies (MAbs) that inhibit infection by HHV-6B. Most of these MAbs were found to recognize gQ1, indicating that HHV-6B gQ1 is critical for virus entry. Interestingly, the recognition of gQ1 by the neutralizing MAb was enhanced by coexpression with gQ2. Moreover, gQ1 deletion or point mutants that are not recognized by the MAb could nonetheless associate with gQ2, indicating that although the MAb recognized the conformational epitope of gQ1 exposed by the gQ2 interaction, this epitope was not related to the gQ2 binding domain. Our study shows that HHV-6B gQ1 is likely a ligand for the HHV-6B receptor, and the recognition site for this MAb will be a promising target for antiviral agents.Human herpesvirus 6 (HHV-6) was first isolated from patients with lymphocytic disorders in1986 (36) and was subsequently shown to be the causative agent of exanthem subitum (ES) (48). Currently, HHV-6 can be classified into two variants, HHV-6A and HHV-6B, based on differences in genetic, antigenic, and growth characteristics and cell tropisms (1,5,7,8). HHV-6B causes infant ES, and more than 90% of people have antibodies (Abs) against HHV-6B (31, 38), while the pathogenesis of HHV-6A is still unknown. Recently, it was shown that a reactivation of HHV-6B causes encephalitis in immunocompromised hosts (13,45,46) and possibly enhances the severity of drug-induced sensitivity syndrome (14).Human CD46, a regulator of the complement activation receptor expressed on all nuclear cells, is a receptor for HHV-6 (37), and its viral ligand is the envelope glycoprotein complex gH/gL/gQ1/gQ2 (3, 28). Although this complex can bind CD46 (28), those of some clinical isolates, including laboratory strains of HHV-6B, do not bind it (24, 26). The gQ gene is unique because it is conserved only among HHV-6A, HHV-6B, and 15,19). Recently, we successfully reconstituted a virus from the HHV-6 genome (43) and found that HHV-6 gQ1 is essential for virus growth and probably for entry.As monoclonal antibodies (MAbs) against gH and gB inhibit virus-induced cell fusion and infection, gH and gB are thought to be fusogenic candidates (39). In addition, as it is common to herpesviruses generally, gH homologues expressed on viral envelopes form a complex with gL homologues (18,20,21).In addition to gH/gL/gQ1/gQ2, another gH/gL complex, gH/ gL/gO, is present in the viral envelopes of both ...

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The Human Herpesvirus 6 U100 Gene Product Is the Third Component of the gH-gL Glycoprotein Complex on the Viral Envelope

Cited by 58 publications

References 46 publications

Interaction of Glycoprotein H of Human Herpesvirus 6 with the Cellular Receptor CD46

Interaction of Glycoprotein H of Human Herpesvirus 6 with the Cellular Receptor CD46

Epstein-Barr Virus gp42 Is Posttranslationally Modified To Produce Soluble gp42 That Mediates HLA Class II Immune Evasion

Analysis of a Neutralizing Antibody for Human Herpesvirus 6B Reveals a Role for Glycoprotein Q1 in Viral Entry

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