human herpesvirus 6 human herpesvirus 6 human herpesvirus 6 (hhv-6) is the common collective name for human betaherpesvirus 6a (hhv-6a) and human betaherpesvirus 6b (hhv-6b). these closely related viruses are two of the nine known herpesviruses that have humans as their primary host. human herpesvirus 6 electron micrograph of one of the hhv6 species hhv-6 released from a lymphocyte which has been infected scientific classification (unranked): virus realm: duplodnaviria kingdom: heunggongvirae phylum: peploviricota class: herviviricetes order: herpesvirales family: herpesviridae subfamily: betaherpesvirinae genus: roseolovirus groups included human betaherpesvirus 6a human betaherpesvirus 6b cladistically included but traditionally excluded taxa all other roseolovirus spp.: human betaherpesvirus 7 macacine betaherpesvirus 9 murid betaherpesvirus 3 suid betaherpesvirus 2 hhv-6a and hhv-6b are double-stranded dna viruses within the betaherpesvirinae subfamily and of the genus roseolovirus. hhv-6a and hhv-6b infect almost all of the human populations that have been tested. hhv-6a has been described as more neurovirulent, and as such is more frequently found in patients with neuroinflammatory diseases such as multiple sclerosis. hhv-6 (and hhv-7) levels in the brain are also elevated in people with alzheimer's disease. hhv-6b primary infection is the cause of the common childhood illness exanthema subitum (also known as roseola infantum or sixth disease). it is passed on from child to child. it is uncommon for adults to contract this disease as most people have had it by kindergarten, and once contracted, immunity arises and prevents future reinfection. additionally, hhv-6b reactivation is common in transplant recipients, which can cause several clinical manifestations such as encephalitis, bone marrow suppression, and pneumonitis. a variety of tests are used in the detection of hhv-6, some of which do not differentiate the two species. history histological slide of the human herpes virus-6 showing infected cells, with inclusion bodies in both the nucleus and the cytoplasm. during 1986, syed zaki salahuddin, dharam ablashi, and robert gallo cultivated peripheral blood mononuclear cells from patients with aids and lymphoproliferative illnesses. short-lived, large, refractile cells that frequently contained intranuclear and/or intracytoplasmic inclusion bodies were documented. electron microscopy revealed a novel virus that they named human b-lymphotrophic virus (hblv). shortly after its discovery, ablashi et al. described five cell lines that can be infected by the newly discovered hblv. they published that hsb-2, a particular t-cell line, is highly susceptible to infection. ablashi's pioneering research concluded by suggesting that the virus name be changed from hblv to hhv-6, in accord with the published provisional classification of herpes viruses. years later, hhv-6 was divided into subtypes. early research (1992) described two very similar, yet unique variants: hhv-6a and hhv-6b. the distinction was warranted due to unique restriction endonuclease cleavages, monoclonal antibody reactions, and growth patterns. hhv-6a includes several adult-derived strains and its disease spectrum is not well defined, although it is thought by some to be more neurovirulent. hhv-6b is commonly detected in children with roseola infantum, as it is the etiologic agent for this condition. within these two viruses is a sequence homology of 95%. in 2012, hhv-6a and hhv-6b were officially recognized as distinct species. taxonomy hhv-6a and hhv-6b were recognized by the international committee on taxonomy of viruses (ictv) as distinct species in 2012. human roseoloviruses include hhv-6a, hhv-6b and hhv-7. herpesvirus was established as a genus in 1971 in the first report of the ictv. this genus consisted of 23 viruses among 4 groups. in 1976, a second ictv report was released in which this genus was elevated to the family level — the herpetoviridae. because of possible confusion with viruses derived from reptiles, the family name was changed in the third report (1979) to herpesviridae. in this report, the family herpesviridae was divided into 3 subfamilies (alphaherpesvirinae, betaherpesvirinae and gammaherpesvirinae) and 5 unnamed genera; 21 viruses were recognized as members of the family. in 2009, the order herpesvirales was created. this was necessitated by the discovery that the herpes viruses of fish and molluscs are only distantly related to those of birds and mammals. order herpesvirales contains three families, the herpesviridae, which contains the long-recognized herpesviruses of mammals, birds, and reptiles, plus two new families — the family alloherpesviridae which incorporates herpes viruses of bony fish and frogs, and the family malacoherpesviridae which contains viruses of molluscs. as of 2012, this order currently has 3 families, 4 subfamilies (1 unassigned), 18 genera (4 unassigned) and 97 species. structure the diameter of an hhv-6 virion is about 2000 angstroms. the virion's outer portion consists of a lipid bilayer membrane that contains viral glycoproteins and is derived from that of the host. below this membrane envelope is a tegument which surrounds an icosahedral capsid, composed of 162 capsomeres. the protective capsid of hhv-6 contains double stranded linear dna. during maturation of hhv-6 virions, human cell membranes are used to form viral lipid envelopes (as is characteristic of all enveloped viruses). during this process hhv-6 utilizes lipid rafts, which are membranous microdomains enriched by cholesterol, sphingolipids, and glycosylphosphatidylinositol-anchored proteins. early researchers suspected that hhv-6 virions mature in the nucleus; some even incorrectly published this, as they generalized and applied to hhv-6 what was known about other viruses. however, researched published in 2009 suggests that the hhv-6 virus utilizes trans-golgi-network-derived vesicles for assembly. genome hhv-6b genome from dominguez et al. 1999the genetic material of hhv-6 is composed of linear (circular during an active infection), double stranded dna which contains an origin of replication, two 8–10 kb left and right direct repeat termini, and a unique segment that is 143–145kb. the origin of replication (often labeled as "orilyt" in the literature) is where dna replication begins. the direct repeat termini (drl and drr) possess a repeated ttaggg sequence, identical to that of human telomeres. variability in the number of telomeric repeats is observed in the range of 15–180. these termini also contain pac-1 and pac-2 cleavage and packing signals that are conserved among herpesviruses. the unique segment contains seven major core gene blocks (u27–u37, u38–u40, u41–u46, u48–u53, u56–u57, u66ex2–u77, and u81–u82), which is also characteristic of herpesviruses. these conserved genes code for proteins that are involved in replication, cleavage, and packing of the viral genome into a mature virion. additionally, they code for a number of immunomodulatory proteins. the unique segment also possesses a block of genes (u2–u19) that are conserved among hhv-6, hhv-7, and cytomegaloviruses (the betaherpesviruses). a number of the unique segment genes are associated with, for instance, the hcmv us22 family (interpro: ipr003360). the table below outlines some of their known properties. genes gene stage properties ie-a (ie1? u89?) immediate early part of ie locus — impairs interferon gene expression to restrict the development of cellular anti-viral measures, favoring a successful infection — not in membrane — activates viral dna polymerases, involved in rolling circle replication — expression of this gene may be modulated by micro rnas ie-b immediate early part of ie locus activates viral dna polymerases, involved in rolling circle replication dr1 hcmv us22 gene family dr6 hcmv us22 gene family, transactivator, oncogene dr7/u1 sr domain, malignant transforming activity, binds to p53 u2 hcmv us22 gene family — tegument protein u3 hcmv ul24 homolog, hcmv us22 gene family, tegument protein — transactivating activity u4 hcmv maribavir resistance u7 hcmv us22 gene family u10 dutpase family u11 strongly immunoreactive virion protein — antigenic tegument protein u12 chemokine g protein-coupled receptor u13 cmv: represses us3 transcription u14 binds and incorporates p53 into viral particles — hcmv ul25 gene family — antigenic tegument protein u15 hcmv ul25 gene family u17 hcmv ul25 gene family — tegument protein u18 ie-b membrane glycoprotein u19 ie-b protein glycoprotein u20 glycoprotein (specific to roseolovirus) predicted immunoglobulin structure u21 binds to mhc-1 molecules and prevents antigen presenting cells from presenting hhv-6 peptides — glycoprotein, downregulates hla i (specific to roseolovirus) u22 late gene glycoprotein (absent from hhv-7, specific to roseolovirus) u23 glycoprotein (specific to roseolovirus) u24 inhibits proper t cell activation, reducing secretion of cytokines at infection site — phosphorylation target for kinases — glycoprotein m (gm) (specific to roseolovirus) u25 hcmv ul22 gene family, tegument protein u26 putative multiple transmembrane protein u27 dna polymerase processivity factory u28 ribonucleotide reductase large subunit, tegument protein u29 capsid assembly and dna maturation u30 tegument protein u31 large tegument protein u32 capsid protein, hexon tips u33 virion protein u34 membrane-associated phosphoprotein, primary envelopment u35 terminase component, dna packaging u36 dna packaging u37 tegument protein, primary envelopment, phosphoprotein u38 dna polymerase u39 (gb, gp116) glycoprotein u40 transport, capsid assembly u41 early gene major dna binding protein u42 tegument protein, cell cycle block, transactivator u43 dna helicase-primase complex u44 tegument protein u45 dutpase u46 glycoprotein n, membrane protein u47 (go, o) glycoprotein o, associates with lipid rafts, exists in two forms, go-120k and go-80k, and go-80k contains complex type n-linked oligosaccharides which are incorporated into viral particles u48 (gh, gp100) glycoprotein gh, virion constituent, part of cd46 gq1/gq2/gl/gh ligand complex, associates with lipid rafts u49 virion-associated regulatory protein, fusion protein u50 dna packaging u51 early gene g protein-coupled chemokine receptor, preventing expression greatly reduces replication — increases intracellular levels of second messenger inositol phosphate, promotes chemotaxis – early gene, along with u41 and u69 u52 u53 protease, capsid assembly protein u54 tegument protein, virion transactivator u55 role in rna synthesis, dutpase u56 capsid protein u57 major capsid protein u58 u59 tegument protein u61 u62 u63 u64 dna packaging: tegument protein u65 tegument protein u66 terminase component u69 early gene tegument protein kinase (ganciclovir kinase) involved in replication u70 alkaline exonuclease u71 myristylated virion protein u72 (gm) glycoprotein m u73 origin-binding protein u74 dna helicase-primase complex u75 tegument protein u76 dna packaging, virion protein u77 helicase-primase complex u79 transcriptional activation u80 predicted immunoglobulin structure u81 uracil-dna glycosylase u82 (gl, gp80) glycoprotein l, virion constituent, part of cd46 gq1/gq2/gl/gh ligand complex, associates with lipid rafts u83 secreted chemotactic (chemoattractant) glycoprotein, binds to chemokine receptors, recruits host cells that secrete chemokines specific to u51 u85 glycoprotein (specific to roseolovirus) u86 ie-2 ie-2 transactivator u88 ie-a u90 ie-a (ie 1) transactivator u91 ie-a, glycoprotein u94 latency (immediate early or early gene) involved in transcriptional repression of lytic genes – aids in the specific integration of hhv-6a/hhv-6b into the telomeres — highly expressed during latency — parvovirus rep homolog (absent in hhv-7) u95 cmv us22 gene family – colocalizes and interacts with the mitochondrial grim-19 protein, an essential component of the oxidative phosphorylation system — binds to nuclear factor-kappa b (nf-κb), deregulation of which has been postulated to contribute to cancer u100 (gp82-105) late gene glycoprotein q, virion constituent, associates with lipid rafts gq1 glycoprotein, complexes with gh and gl to form viral ligand to cd46 receptor – modified by n-glycosylation — expressed in two different forms: an 80-kda form (gq1-80k) and a 74-kda form (gq1-74k) – only gq1-80k, but not gq1-74k, forms the cd46 ligand complex with gq2, gh, and gl associates with lipid rafts. gm1 lipid-raft-specific ganglioside, incorporated into virion gq2 glycoprotein, forms gh/gl/gq1/gq2 complex, part of receptor ligand – essential for viral growth, associates with lipid rafts — exists in two forms: gq2-34k and gq2-37k micro rnas hhv6b-mir-ro6-1, -ro6-2, -ro6-3, and -ro6-4. may regulate early transcription p100 aka p101 immunogenic, constituent of tegument orf-1 (dr7) binds and inhibits transcriptional activity of p53 – can transform human epidermal keratinocytes and nih 3t3 cells in vitro – cells expressing orf-1 protein produce fibrosarcomas when injected into nude mice viral entry hhv-6 receptor when an extracellular hhv-6 virion comes across human cells, it encounters the human receptor protein cluster of differentiation 46 (cd46), which plays a role in regulating the complement system. the cd46 protein possesses a single variable region, as a result of alternative splicing. as such, at least fourteen isoforms of cd46 exist, all of which bind hhv-6a. the extracellular region of cd46 contains four short consensus repeats of about 60 amino acids that fold into a compact beta-barrel domain surrounded by flexible loops. as has been demonstrated for cd46 with other ligands, the cd46 protein structure linearizes upon binding hhv-6. while their precise interaction has not yet been determined, the second and third scr domains have been demonstrated as required for hhv-6 receptor binding and cellular entry. hhv-6 receptor ligand mori et al. first identified the gene product gq1, a glycoprotein unique to hhv-6, and found that it forms a complex with gh and gl glycoproteins. they believed that this