Variations in the Replication and Antigenic Properties of Human Herpesvirus 6 Strains

Wyatt, Linda S.; Balachandran, N.; Frenkel, Niza

doi:10.1093/infdis/162.4.852

Cited by 123 publications

(71 citation statements)

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“…There appear to be some growth differences between the groups, although these may be strain-specific. Comparative studies show growth of some isolates in different CD4 + T leukaemic cell lines: group A isolates in HSB2 cells, and group B isolates in MOLT3 cells (Wyatt et al, 1990;Ablashi et al, 1991;Schirmer et al, 1991;Chandran et al, 1992;Dewhurst et al, 1992). It has been suggested that the HHV-6 strain variant groups be reclassified (Schirmer et al, 1991), but the molecular basis of the grouping has not been determined and therefore it is not clear whether this represents variation between strains or new species.…”

Section: Introductionmentioning

confidence: 99%

Two groups of human herpesvirus 6 identified by sequence analyses of laboratory strains and variants from Hodgkin's lymphoma and bone marrow transplant patients

Gompels

Carrigan

Carss

et al. 1993

Journal of General Virology

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Fifteen human herpesvirus 6 (HHV-6) strain variants were analysed by PCR amplifications, restriction enzyme site polymorphism and sequence analyses. Three DNA regions were chosen for study: a fragment of a variable glycoprotein gene (210 bp), the conserved glycoprotein H (gH) gene complete with intergenic sequences (2381 bp) and the 5' intergenic region with the Nterminal coding sequence of gH up to a polymorphic BamHI site (427 bp). Infected cell DNA from five laboratory reference strains including GS, Ul102, AJ, Z29 and KF were examined together with DNA from peripheral blood lymphocytes infected with HHV-6 reactivated from blood and/or marrow from five bone marrow transplant (BMT) patients. Separate blood and marrow isolates were obtained from four BMT patients. In addition, HHV-6 sequences were examined directly from one of six Hodgkin's lymphomas and six B cell proliferations which contained HHV-6 DNA as detected by PCR amplification. The results show two groups of very closely related but heterogeneous strains which correlate with previous groupings by antigenic and restriction site differences. These are variant A strains (including laboratory strains GS, Ul102 and AJ) and variant B strains (including laboratory strains Z29 and KF, the Hodgkin's lymphoma strain, and the nine BMT patient isolates). Variations between the groups were 4 to 6 % in nucleotide sequence and 5 to 8.5 % in amino acid sequence. Within each group maximum heterogeneity was observed in different genes. Variant A strains differed by 2-0% in the variable glycoprotein gene sequence whereas variant B strains were identical in this region; conversely, variant B strains differed by 2 to 3 % in the gH N-terminal and intergenic sequences whereas variant A strains differed there by less than 0'2%. There was evidence for sequence drift independent of selection: relationships between the groups were shown by analyses of amino acid sequence, coding nucleotide sequence as well as intergenic sequence, and the B variant-specific BamHI site in the gH gene was due to a non-coding nucleotide substitution. There was little evidence for in vivo or in vitro variation: the gH nucleotide sequence from the uncultured lymphoma strain (first variant B gH gene identified) was almost identical to the gH sequence from four BMT isolates, and matched BMT isolates from blood and marrow were identical or with a single nucleotide substitution. The overall variation observed between the HHV-6 strain groups was similar or less than that seen between human cytomegalovirus strains such as AD169 or Towne, but deafly distinct from the much greater divergence between currently designated herpesvirus species.

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Section: Introductionmentioning

confidence: 99%

Two groups of human herpesvirus 6 identified by sequence analyses of laboratory strains and variants from Hodgkin's lymphoma and bone marrow transplant patients

Gompels

Carrigan

Carss

et al. 1993

Journal of General Virology

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“…HHV-6 was first isolated from the peripheral blood lymphocytes of patients with lymphoproliferative disorders and AIDS (34). HHV-6 isolates can be categorized as two variants, A (HHV-6A) and B (HHV-6B), on the basis of their in vitro growth properties, DNA restriction site polymorphisms, antigenicity, and host cell tropism (1,(3)(4)(5)45). HHV-6B is the causative agent of exanthem subitum (46).…”

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confidence: 99%

Intracellular Processing of Human Herpesvirus 6 Glycoproteins Q1 and Q2 into Tetrameric Complexes Expressed on the Viral Envelope

Akkapaiboon

Mori

Sadaoka

et al. 2004

J Virol

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Human herpesvirus 6 (HHV-6) glycoproteins H and L (gH and gL, respectively) and the 80-kDa form of glycoprotein Q (gQ-80K) form a heterotrimeric complex that is found on the viral envelope and that is a viral ligand for human CD46. Besides gQ-80K, the gQ gene encodes an additional product whose mature molecular mass is 37 kDa (gQ-37K) and which is derived from a different transcript. Therefore, we designated gQ-80K as gQ1 and gQ-37K as gQ2. We show here that gQ2 also interacts with the gH-gL-gQ1 complex in HHV-6-infected cells and in virions. To examine how these components interact in HHV-6-infected cells, we performed pulse-chase studies. The results demonstrated that gQ2-34K, which is endo-␤-N-acetylglucosaminidase H sensitive and which is the precursor form of gQ2-37K, associates with gQ1-74K, which is the precursor form of gQ1-80K, within 30 min of the pulse period. After a 1-h chase, these precursor forms had associated with the gH-gL dimer. Interestingly, an anti-gH monoclonal antibody coimmunoprecipitated mainly gQ1-80K and gQ2-37K, with little gQ1-74K or gQ2-34K. These results indicate that although gQ2-34K and gQ1-74K interact in the endoplasmic reticulum, the gH-gL-gQ1-80K-gQ2-37K heterotetrameric complex arises in the postendoplasmic reticulum compartment. The mature complex is subsequently incorporated into viral particles.Human herpesvirus 6 (HHV-6) is a betaherpesvirus related to human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV) and is a human pathogen of emerging clinical significance. HHV-6 was first isolated from the peripheral blood lymphocytes of patients with lymphoproliferative disorders and AIDS (34). HHV-6 isolates can be categorized as two variants, A (HHV-6A) and B (HHV-6B), on the basis of their in vitro growth properties, DNA restriction site polymorphisms, antigenicity, and host cell tropism (1,(3)(4)(5)45). HHV-6B is the causative agent of exanthem subitum (46).Herpesviruses encode a number of glycoproteins that are present in the envelope of the virion and that play an important role in viral infection, including attachment, penetration, cell-cell spread, and the envelopment and maturation of nascent viral particles. A number of studies have reported a role for glycoprotein H (gH) and glycoprotein L (gL) in the membrane fusion events involved in herpesvirus entry and cell-cell spread. Monoclonal antibodies (MAbs) raised to gH neutralize the activity of infectious virus (6,10,12,13,22,23,37). Similarly, antibodies against gL can inhibit virus infectivity and cell fusion (19,29,30).Previous studies showed that gH and gL form a heteromeric glycoprotein complex (11,17,18,22,33,47). Intermolecular disulfide bridges are required for complex formation in betaherpesviruses HCMV and HHV-6 (2, 18, 38) but not in alphaherpesviruses herpes simplex virus type 1, varicella-zoster virus, and bovine herpesvirus 1 (8,9,17,42). The Epstein-Barr virus (EBV) gH-gL complex includes a third glycoprotein, called gp42, which is encoded by the BZLF2 open reading frame (ORF) (21). The gCIII compl...

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“…HHV-6B is the causal agent of exanthem subitum (62). The two variants can be differentiated on the basis of genomic polymorphism, antigenicity, and host cell tropism (1,3,7,61).…”

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confidence: 99%

Human Herpesvirus 6 Variant A but Not Variant B Induces Fusion from Without in a Variety of Human Cells through a Human Herpesvirus 6 Entry Receptor, CD46

Mori

Seya

Huang

et al. 2002

J Virol

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Human herpesvirus 6 (HHV-6) is a lymphotropic betaherpesvirus that productively infects T cells and monocytes. HHV-6 isolates can be differentiated into two groups, variants A and B (HHV-6A and HHV-6B). Here, we show a functional difference between HHV-6A and -6B in that HHV-6A induced syncytium formation of diverse human cells but HHV-6B did not. The syncytium formation induced by HHV-6A was observed 2 h after infection; moreover, it was found in the presence of cycloheximide, indicating that HHV-6A induced fusion from without (FFWO) in the target cells. Furthermore, the fusion event was dependent on the expression of the HHV-6 entry receptor, CD46, on the target cell membrane. In addition, we determined that short consensus repeat 2 (SCR2), -3, and -4 of the CD46 ectodomain were essential for the formation of the virus-induced syncytia. Monoclonal antibodies against glycoproteins B and H of HHV-6A inhibited the fusion event, indicating that the syncytium formation induced by HHV-6A required glycoproteins H and B. These findings suggest that FFWO, which HHV-6A induced in a variety of cell lines, may play an important role in the pathogenesis of HHV-6A, not only in lymphocytes but also in various tissues, because CD46 is expressed ubiquitously in human tissues.

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Variations in the Replication and Antigenic Properties of Human Herpesvirus 6 Strains

Cited by 123 publications

References 0 publications

Two groups of human herpesvirus 6 identified by sequence analyses of laboratory strains and variants from Hodgkin's lymphoma and bone marrow transplant patients

Two groups of human herpesvirus 6 identified by sequence analyses of laboratory strains and variants from Hodgkin's lymphoma and bone marrow transplant patients

Intracellular Processing of Human Herpesvirus 6 Glycoproteins Q1 and Q2 into Tetrameric Complexes Expressed on the Viral Envelope

Human Herpesvirus 6 Variant A but Not Variant B Induces Fusion from Without in a Variety of Human Cells through a Human Herpesvirus 6 Entry Receptor, CD46

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