Comp. lmmun. Microbiol. infect. Dis. Vol. 14, No. 2, pp. 63-79, 1991 Printed in Great Britain.All rights reserved

0147-9571/91 $3.00+ 0.00 Copyright © 1991PergamonPress plc

THE DIVERSITY A N D UNITY OF H E R P E S F I R I D A E BERNARD ROIZMAN a n d JOEL BAINES The Majorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 East 58th Street, Chicago, IL 60637, U.S.A. Abstract--The family herpesviridae contains over 100 viruses endogenous to humans and to a wide variety of eukaryotic organisms. Inclusion in the family is based on architecture of the virion. The viruses differ significantly with respect to base composition and sequence arrangements of their DNAs, but share many biologic properties including the ability to remain latent in their hosts. On the basis of their biologic properties the herpesviruses have been classified into three subfamilies, i.e. alphaherpesvirinae, betaherpesvirinae and gammaherpesvirinae. The members of each subfamily share many properties including greater conservation and colinear arrangements of their genes. As a rule, more than one herpesvirus has been isolated from animals of economic importance and both humans have yielded viruses belong to all three subfamilies of the herpesviridae.

Key words: definition, classification, virion components, genome properties. D I V E R S I T E ET U N I T E DES HERPESVIRIDAE Rrsumr---La famille des herpesviridae comporte plus de 100 virus, h6tes de l'homme et d'organismes eucaryotes trrs divers. L'appartenance ~ cette famille se fonde sur rarchitecture du virion. Les virus prrsentent de grandes diffrrences dans la composition en bases et dans l'arrangement des srquen,:es de leur ADN mais ils ont en commun plusieurs proprirtrs biologiques dont l'aptitude fi demeurer latente chez leurs h6tes. En se fondant sur leurs proprirtrs biologiques, les herpesvirus ont 6t6 classrs en trois sous-familles,les alphaherpesvirinae, les betaherpesvirinae et les gammaherpesvirinae. Les membres de chaque sous-famille ont plusieurs proprirtrs communes, dont une disposition coli:araire et une grande conservation de grnes. D'une manirre grnrrale, on a isol6 plusieurs herpesvirus chez les animaux qui ont une importance 6conomique; on a trouv6 chez I'homme des virus des trois sous-familles d'herpesviridae.

Mots-clefs: drfinition, classification, constituants viraux, proprirtrs du grnome.

" G o d n o t only plays dice. Sometimes he also throws them where they c a n n o t be seen". Stephen William H a w k i n g , Nature 257, 362 (1975)

INTRODUCTION Herpesviruses are highly disseminated in n a t u r e a n d most a n i m a l species have yielded at least one herpesvirus u p o n e x a m i n a t i o n . O f the 100 + herpesviruses which have been at least partially characterized, seven herpesviruses have been isolated from h u m a n s , five from horses, at least four from cattle, two from pigs, a n d three from chickens. The list o f currently k n o w n herpesviruses compiled in part by the Herpesvirus Study G r o u p o f the I n t e r n a t i o n a l C o m m i t t e e for the T a x o n o m y o f Viruses is shown in T a b l e 1 [1-180]. Viruses included in the family Herpesviridae share several properties. They c o n t a i n a D N A genome, a n architecturally similar virion, a n d they can m a i n t a i n themselves in a latent state for the life o f the host. They differ significantly with respect to (i) properties 63

64

BERNARD ROIZMAN and JOEL BAINES Table 1. Selected viruses of the family herpesviridae Genome Subfamily properties

Designation Viruses of humans Human herpesvirus 1 Human herpesvirus 2 Human herpesvirus 3 Human herpesvirus 4 Human herpesvirus 5 Human herpesvirus 6 Human herpesvirus 7 Viruses of non-human primates$ Aotine herpesvirus 1 Aotine herpesvirus 2 Cereopithecine herpesvirus 1 Cercopithecine herpesvirus 2 Cereopithecine herpesvirus 3 Cercopithecine herpesvirus 4 Cercopitheeine herpesvirus 5 Cercopithecine herpesvirus 6 Cercopithecine herpesvirus 7 Cercopithecine herpesvirus 8 Cercopithecine herpesvirus 9 Cercopithecine herpesvirus 10 Cercopithecine herpesvirus 11 Cercopithecine herpesvirus 12 Cercopithecine herpesvirus t3 Cercopithecine herpesvirus 14 Cercopithecine herpesvirus 15 Ateline herpesvirus 1 Ateline herpesvirus 2 Ateline herpesvirus 3 Canitrichine herpesvirus 1 Callitrichine herpesvirus 2 Cebine herpesvirus I Cebine herpesvirus 2 Pongine herpesvirus I Pongine herpesvirus 2 Pongine herpesvirus 3 Saimiriine herpesvirus I Saimiriine herpesvirus 2 Tupaiaine herpesvirus 1 Viruses of other mammals Bovidae* Bovine herpesvirus 1 Bovine herpesvirus 2 Bovine herpesvirus 4~ Bovine herpesvirus 5 Ovine herpesvirus 1 Caprine herpesvirus 1

G + C typet; size (mol %) (Kbp)

Common name (synonyms) Herpes simplex virus I Herpes simplex virus 2 Varicena-zoster virus Epstein-Barr virus Cytomegalovirus

ct • ~t 7 fl fl

67 69 46 60 57 42

E; 152 E: 152 D; 125 C; 172 E; 229 A; 170

[1-4] [3, 4] [5-7] [8-10] [11-13] [14, 15] [161

E; B; E; E:

[17, 18] [19,20] [211 [22] [22, 231 [23] [24l

fl HV aotus type 1 HV aotus type 2 B virus, HV simiae SA8 SA6 SA15 African green monkey cytomegalovirus (AGM-CMV) Liverpool vervet monkey virus (LVMV or LVV) Patas monkey HV; MMV or PHV delta HV Rhesus monkey cytomegalovirus Medical Lake macaque HV; simian varicena virus Rhesus leukocyte assoc. HV strain I (551 I) Rhesus leukocyte assoc. HV strain II (533 I) HV papio, baboon HV Herpesvirus cyclopsis African green monkey EBV-like virus (AGM-EBV) Rhesus EBV-like HV Spider monkey HV HV ateles strain 810 HV ateles strain 73 HV sanguinus SSG, marmoset cytomegalovirus Capuchin HV (AL-5) Capuchin HV (AP-18) Chimpanzee HV; pan HV Orangutan HV Gorilla HV Marmoset HV; herpes M, herpes T, HV tamarinus, HV platyrrhinae type 1 Squirrel monkey HV, HV saimiri Tree shrew' herpesvirus

fl y ~ g ~ /~ fl

--75 67 51

~t

52

Infectious bovine rhinotracheitis virus Bovine mammiUitis virus Allerton virus, pseudolumpy skin disease virus Movar HV Bovine encephalitis HV Sheep HV Goat HV

145 t50 160 150

[25]

~t fl ct

References

[26] 52

[27] [28]

7

[29]

~

[29]

"/

C; 170

~ ~, a 7 7 fl fl fl I, ~, 7 ~t

72 48

B; 135

C; 170

[30, 31] [32] [33] [34] [22, 35] [36, 37] [38] [39] [40] [411 [21] [30, 42] [43] [441 [22] [45] [46] [47] [48-50]

67

D/E; 152

46 66

B; 155 F; 200

ct

72

D; 140

[51-53]

~t

64

E; 133

[52, 54-57]

7 ~

50 72

B; 145 D; 140 D; 137

[58-61] [62-64] [65-67] [68, 69]

y

~t

(Table I continued opposite)

Family herpesviridae

65

Table I (continued) Genome Subfamily properties Designation Alcelaphine herpesvirus 1 Aledaphine herpesvirus 2 Cervid herpesvirus I Cervid herpesvirus 2 Canidae Canid herpesvirus I Caviidae Caviid herpesvirus I Caviid herpesvirus 2 Caviid herpesvirus 3 Cricetidae Cricetid herpesvirus Elephanitidae Elephantid herpesvirus Equidae Equid herpesvirus I Equid herpesvirus 2 Equid herpesvirus 3 Equid herpesvirus 4 Equid herpesvirus 5 Equid herpesvirus 6 Equid herpesvirus 7 Equid herpesvirus 8 Felidae§ Felid herpesvirus 1

Leporidae Leporid herpesvirus 1 Leporid herpesvirus 2 Lorisidae Lorisine herpesvirus I Macropodidae Macropodid herpesvirus I Macropodid herpesvirus 2 Marmodidae Marmodid herpesvirus I

Muridae Murid herpesvirus 1 Murid herpesvirus 2 Murid herpesvirus 3 Murid herpesvirus 4 Murid herpesvirus 5 Murid herpesvirus 6 Murid herpesvirus 7 Phocidae Phocid herpesvirus I Sciuridae Sciurid herpesvirus 1 Sciurid herpesvirus 2

G + C type'['; size (mol %) (Kbp)

Common name (synonyms)

~, a a

Canine HV

•

32

[771

Guinea pig HV I, Hsiung -Kaplow virus, GPHLV Guinea pig cytomegalovirus Guinea pig HV 3, GPXV

r

60

[78-801

fl

57

[81,821

Hamster HV

7

61

References

Wildebeest HV malignant catarrhal fever of European cattle Hartebeest HV Red deer HV Reindeer (Rangifer tarandus HV)

B; 160

[70-721

B; D; D;

[73] [74, 75] [76]

[83] fl

[841

Elephant (Ioxodontal) HV Equine HV 1; equine abortion virus Equine HV 2; equine cytomegalovirus Equine HV 3; equine coital-exanthema virus Equine HV 4; equine rhinopneumonitis virus Equine HV 5 Asinine HV I Asinine HV 2 Asinine HV 3

[85, 86] a

57

D; 142

[87-89]

/3

57

A; 192

[9o-921

a

66

D; 148

[93-951

a

56

D; 148

[96-98]

150

[99] [i00l [i01l [1011

// a fl ct

Feline HV 1; infectious feline rhinotracheitis HV

c¢

46

B; 134

[86, 102, 1031

Cottontail HV, HV sylvilagus HV cuniculi, virus III

y

33

B; 145

[22, 104-106] [106]

Kinkajou HV, herpes pottos

[107]

Parma wallaby HV Dorcopsis wallaby HV

a a

Woodchuck HV HV marmota I

~

Mouse cytomegalovirus Rat cytomegalovirus Mouse thymic virus Mouse HV strain 68 Field mouse HV; Microtus pennsylvanicus HV Sand rat nuclear inclusion agents Murine alphaherpesvirus

// //

D; E; 135

[108, 109] [109, i 10]

B; 160

Jill, 1121

59 47

F; 132

7

60

B: 135

[113, 1141 [115, 1161 [117, 1181 [119-121] [122]

a

60

Harbor seal herpesvirus European ground squirrel cytomegalovirus American ground squirrel HV

53 50

[1231 [119, 124] [125, 1261

fl

[127, 1281 [129]

(Table I continued overleaf)

BERNARD ROIZMAN and JOEL BAINES

66

Table I (continued) Genome Subfamily properties Designation Suidae Suid herpesvirus 1

Suid herpesvirus 2 Viruses of birds Anatidae Anatid herpesvirus 1 Accipitriae Accipitrid herpesvirus 1 Ciciniidae Ciconiid herpesvirus 1 Columbidae Columbid herpesvirus 1 Falconidae Falconid herpesvirus 1 Gallidae Gallid herpesvirus 1 Gallid herpesvirus 2 Gallid herpesvirus 3 Gruidae Gruid herpesvirus 1 Melagridae Meleagrid herpesvirus 1 Perdicid Perdicid herpesvirus 1 Phalacrocoracidae Phalacrocoracid herpesvirus 1 Psittacidae Psittacid herpesvirus I Sphenicidae Sphenicid herpesvirus 1" Stricidae Strigid herpesvirus I Viruses of amphibia and reptiles Boidae Boid herpesvirus 1¶1 Chelonidae Chelonid herpesvirus Itl

Chelonid herpesvirus 2¶1 Chelonid herpesvirus 3¶1 Chelonid herpesvirus 4¶1 Elapidae Elapid herpesvirus Iguanidae Iguanid herpesvirus 1 Lacertidae Lacertid herpesvirus I Ranidae Ranid herpesvirus 1 Ranid herpesvirus 2

G + C typeJ'; size (mol %) (Kbp)

Common name (synonyms)

74

D; 140

References

Pseudorabies virus, Aujeszky's disease Inclusion-body rhinitis virus, pig cytomegalovirus

a

[130, 131]

/~

[132, 133]

Duck plague HV

ct

[134, 135]

Bald eagle HV

[136]

Black stork HV

[137]

Pigeon HV-I

59

[138, 139]

Falcon inclusion body disease virus Infectious laryngotracheitis virus Marek's disease HV 1 Marek's disease HV 2

[140] •

46 47

D; 165 E; 180

Crane HV Turkey HV 1

[86, 139, 141,142] [143-146] [147, 148] [149]

?

48

Bobwhite quail HV Cormorant HV; Lake Victoria cormorant HV

E; 150

[139, 150] [151]

58

[139, 152]

Parrott HV; recently rediscovered Pacheco's disease virus

[153]

Black footed penguin HV

[154]

Owl hepatosplenitis virus

61

Boa herpesvirus

[139, 155, 156]

[157]

Gray patch disease agent of green seas turtle Pacific pond turtle HV Painted turtle HV map turtle HV Geochelone chilensis HV, Geochelone carbonaria HV, Argentine turtle HV

[158, 159] [1601 [161,162] ]163]

Indian cobra, banded krait, siamese cobra

[164, 165]

Green iguana HV

[166, 167]

Green lizard HV Lucke frog HV Frog HV 4

[168] 46 56

[169-171] [171, 1721 (Table 1 continued opposite)

67

F a m i l y herpesviridae Table 1 (continued) Genome Subfamily properties Designation

Common name (synonyms)

G + C type$; size (mol %) (Kbp)

References

Viruses of bony fishes Cyprinidae Cyprinid herpesvirus

Carp pox HV

[173]

Northern pike herpesvirus

1174]

Esocidae Esocid herpesvirus ¶

Ictaluridae lctalurid herpesvirus 1

Channel catfish HV

ct

56

A; 86

[175, 176]

Percidae Percid herpesvirus 1

Walleye epidermal hyperplasia virus

[177]

Pleuronectidae Pleuronectid herpesvirus

HV scophthalmus, turbot HV

Salmonidae Salmonid herpesvirus 1 Salmonid herpesvirus 2

HV salmonis

Oncorhynchus masou HV

[1781 [179] 11801

*Bovine herpesvirus 3 sometimes referred to as bovine herpesvirus 4 does not exist now. These designations were applied to the virus acquired from the wildebeest; it causes malignant catarrhal fever in cattle and is now called Alcephanine herpesvirus 1. tLetters A-F identify genome arrangements described in the text. :~Scheldrick P., Bertbelot N., Laithier M. and Fleckenstein B. Personal communication. §Feline herpesvirus 2, and a virus isolated from sheep have all been identified as BHV4. In accordance with the rules this number cannot be assigned to another herpesvirus. ¶Indicates reports of herpesvirus-like particles in tissues but not isolation in cell culture.

of their DNAs, (ii) gene content and linear arrangement of the genes in viral genomes, (iii) host range and duration of the reproductive cycle, and (iv) the mechanism by which the viruses maintain the latent state in the host. A typical herpesvirion consists of a core containing a linear double stranded DNA, a capsid surrounded by the tegument, and an envelope containing viral glycoprotein spikes on its surface. ARCHITECTURE OF THE HERPESVIRION The core

In the virion, the DNA is arranged in the form of a toroid [181,182]. In some electron micrographs, the torus appears to be supported by a proteinaceous spindle consisting of fibrils imbedded in the underside of the capsid and passing through the hole of the torus. The precise arrangement of the DNA in the toroid is not known. The capsid

Characteristically, the capsid of all herpesviruses have a diameter of 100-110 nm. The 150 hexameric capsomeres are 9.5 x 12.5 nm in longitudinal section; an open channel 4 nm in diameter runs part way from the surface along the long axis [183]. The 12 pentameric capsomeres at the vertices have not been well characterized. The tegument

The tegument, a term introduced by Roizman and Furlong [184] to describe the structures between the capsid and envelope, has no distinctive features in thin sections, but may appear to be fibrous on negative staining [183, 185, 186]. The tegument is frequently distributed asymmetrically and its thickness may vary depending on the location of the

68

BERNARDROIZMANand JOEL BAINES

virion within the infected cell. In the guinea pig herpesvirus, for example, thickness of the tegument is greater in virions accumulating in cytoplasmic vacuoles than in those accumulating in the perinuclear space [187]. The available evidence suggests the amount of tegument is more likely to be determined by the virus than by the host [188].

The envelope The herpesvirus envelope has a typical trilaminar appearance [189]. It appears to be derived from patches of altered cellular membranes [186, 190, 191]. The presence of lipids was demonstrated by analyses of virions [192, 193] and by the sensitivity of the virions to lipid solvents and detergents [194-196]. The herpesvirus envelope contains numerous spikes consiting of virus specific glycoproteins. The spikes are more numerous than those appearing on the surface of many other enveloped viruses. Wildy and Watson estimated that the spikes protruding from the surface of the herpesvirions are approx. 8 nm long [183]. The number and relative amounts of viral glycoproteins vary; herpes simplex virus specifies at least 8 glycoproteins. Some herpesviruses specify a far greater number of glycosylated proteins, but not all glycoproteins become components of the envelope.

The virion The precise number of polypeptide species contained in the herpesvirions is not known and may vary from one virus to another. It has been estimated that the herpesvirion contains at least 30-35 protein species. The uncertainty stems in part from the inability to determine whether proteins made early in infection and association with virions in small amounts are true components of the virion or contaminants. Herpesvirions have been reported to range from 120 to nearly 300 nm in diameter (reviewed in Ref. [184]). The major source of variability is the state of the envelope. Intact envelopes are impermeable and generally retain the quasi-spherical shape of the virion. Damaged envelopes are permeable to negative stains; permeated virions have a sunny-sideup egg appearance with a diameter much larger than that of an intact virion. THE HERPESVIRUS GENOMES

Base composition, size, and arrangement of reiterations of DNA sequence The bulk of herpesvirus DNAs extracted from virions are linear and double stranded, but they circularize immediately upon release from capsids into the nuclei of infected cells [197]. The base composition of herpesvirus DNAs varies from 31 to 75 G + C mol % (Table 1). Furthermore, herpesvirus DNAs vary with respect to the extent of homogeneity of base sequence distribution across the length of the genome. The extent of inhomogeneity may be very high (e.g. the DNAs of herpes saimiri and herpes ateles; see Ref. [198]). The molecular weight of herpesvirus DNAs varies from approx. 80 to 150 million, or from approx. 120 to 230 kbp (Table 1). The variability in the size of herpesvirus DNAs does not reflect a polymorphism in the size of DNAs of individual viruses. The variation in the size of the genome of any one herpesvirus appears to be minimal, but not insignificant. Thus, many viral DNAs contain terminal and internal reiterated sequences. Because of variability in the number of these reiterations, the size of individual genomes may vary by > 10 kbp. Spontaneous deletions also occur; they have been noted in both HSV and EBV strains passaged outside the human host (e.g. EBV strain P3HR1, HSV strain HFEM).

Family herpesviridae

69

As noted above, most herpesvirus DNAs contain reiterations of some of their sequences. As reviewed elsewhere [3], the arrangment of these reiterations vary. On the basis of the arrangement of reiterations of sequences > 100 bp length the herpesviruses can be divided into six groups designated by the letters A-F. In the genomes of viruses comprising group A and exemplified by the channel catfish herpesvirus, a large sequence from one terminus is directly repeated at the other terminus. In the group B genomes exemplified by herpes saimiri virus, the terminal sequence is directly repeated numerous times at both termini, and furthermore, the number of reiterations at both termini may vary. In the group C genomes exemplified by that of Epstein-Barr virus, the number of direct terminal reiterations is smaller, but there may be other, unrelated, sequences > 100 bp that are directly repeated and which subdivide the unique (or quasi unique) sequences of the genome into several well delineated stretches. In group D genomes exemplified by that of equine herpesvirus 1, the sequences from one terminus are repeated in an inverted orientation internally. In these genomes, the domain consisting of the stretch of unique sequences flanked by inverted repeats (Small or S component) can invert relative to the remaining sequences (Large or L component) such that the DNA extracted from virions or infected cells consists of two equimolar populations differing solely in the relative orientation of the S component relative to the L component. In group E viral genomes exemplified by those of herpes simplex virus, sequences from both termini are repeated in an inverted orientation and juxtaposed internally dividing the genomes into two components each of which consists of unique sequences flanked by inverted repeats. In this instance, both components can invert relative to each other and DNA extracted from virions or infected cells consists of four equimolar populations differing in the relative orientation of the two components. In the genomes comprising the F group (e.g. tupaia herpesvirus). The sequences at the two termini are not identical and are not repeated directly or in an inverted orientation.

BIOLOGICAL PROPERTIES OF HERPESVIRUSES The known herpesviruses appear to share four significant biological properties [3]: (i) All herpesviruses specify a large array of enzymes involved in processing of proteins and in nucleic acid metabolism. These may include a protease, protein kinase, thymidine kinase, thymidylate synthetase, dUTPase, ribonucleotide reductase, DNA polymerase, helicase, primase, etc. Although all herpesviruses specify a DNA polymerase and other proteins involved in DNA synthesis, the exact array of enzymes may vary from one herpesvirus to another. (ii) The synthesis of viral DNAs and assembly of capsids occur in the nucleus. In the case of some herpesviruses, it has been claimed that the virus may be de-enveloped and re-enveloped as it transits through the cytoplasm. Irrespective of the merits of these conclusions, envelopment of the capsids as it transits through the nuclear membrane is obligatory. (iii) Production of infectious progeny virus is invariably accompanied by the irreversible destruction of the infected cell. (iv) The herpesviruses examined to date are able to remain latent in their natural hosts. In cells harboring latent virus, the viral genomes take the form of closed circular molecules and only a small subset of viral genes is expressed.

70

BERNARD ROIZMANand JOEL BA1NES

Herpesviruses also vary greatly in their biologic properties. Some have a wide cell host range, multiply efficiently, and rapidly destroy the cells which they infect (e.g. herpes simplex virus 1 and 2, pseudorabies virus, etc.). Others have a narrow cell host range (e.g. human herpesvirus No. 6). The multiplication of some herpesviruses appears to be slow (human cytomegalovirus). While all herpesviruses remain latent in a specific set of cells, the exact cell in which they remain latent varies from one virus to another. For example, whereas latent HSV is recovered from sensory neurons, latent Epstein-Barr virus is recovered from B lymphocytes. Herpesviruses differ with respect to the clinical manifestations of diseases they cause. CLASSIFICATION OF HERPESVIRUSES The members of the family herpesviridae have been classified by the Herpesvirus Study Group of the International Committee on the Taxonomy of Viruses (ICTV) into three sub-families, i.e. the alphaherpesvirinae, the betaherpesvirinae and the gammaherpesvirinae, on the basis of biologic properties [199]. The Study Group has also classified a small number of herpesviruses into genera based on DNA sequence homology, similarities in genome sequence arrangement, and relatedness of important viral proteins demonstrable by immunologic methods. While a few genes (e.g. homologs of glycoprotein B of HSV-1 [55, 200] or of glycoprotein H [201]) are conserved among members of different subfamilies, nucleic acid and protein sequence homologies are particularly useful for the classification of viruses that are closely related (genera). The recommendations of the Study Group endorsed by ICTV is that herpesviruses be designated by serial arabic number and the family (most cases) or subfamily (for primates and some animals) in which the natural host of the virus is classified (e.g. human herpesvirus No. 6, circopithecine herpesvirus 1, etc.; see Table 1). A formal binomial nomenclature is not currently applied.

A lphaherpesvirinae The members of this subfamily are classified on the basis of a variable host range, relatively short reproductive cycle, rapid spread in culture, efficient destruction of infected cells, and capacity to establish latent infections primarily but not exclusively in sensory ganglia. This subfamily contains the genera simplexvirus (HSV-1, HSV-2, circopithecine herpesvirus 1, bovine mammiUitis virus) and varicellovirus (VSV, pseudorabies virus, and equine herpesvirus 1).

Betaherpesvirinae A nonexclusive characteristic of the members of this subfamily is a restricted host range. The reproductive cycle is long and the infection progresses slowly in culture. The infected cells frequently become enlarged (cytomegalia) and carrier cultures are readily established. The virus can be maintained in latent form in secretory glands, lymphoreticular cells, kidneys and other tissues. This subfamily contains the genera cytomegalovirus (HCMV) and muromegalovirus (murine cytomegalovirus).

Gammahe rpesv irinae The experimental host range of the members of this subfamily is limited to the family or order to which the natural host belongs. In vitro all members replicate in lymphoblastoid

Family herpesviridae

71

cells and some also cause lytic infections in some types of epithelioid and fibroblastic cells. Viruses in this group are specific for either T or B lymphocytes. In the lymphocyte, infection is frequently either at a pre-lytic or lytic stage, but without production of infectious progeny. Latent virus is frequently demonstrated in lymphoid tissue. This subfamily currently contains two genera, i.e. lymphocryptovirus (e.g. EBV), and rhadinovirus (herpesvirus ateles and herpesvirus saimiri). To reiterate a statement made elsewhere [3], the current classification of herpesviruses is at once simple, fortuitously appropriate, and defective. The purpose of classifying viruses into subfamilies and genera is multifold. While a classification scheme is often used to depict evolutionary relatedness, it also serves a practical purpose of enabling the laboratory worker to predict the properties and identity of a new isolate. The classification of new isolates by the current criteria can be performed rapidly and without extensive application of expensive and laborious molecular biological tools. The key defect of the current classification is that it is not based on objective criteria that serve a useful function in defining evolutionary relatedness. The objective criteria that have been proposed for the classification of herpesvirus subfamilies are (i) conservation of genes and gene clusters (e.g. DNA polymerase, glycoproteins B, C and H, single strand DNA binding protein, major capsid protein, etc.) and arrangement of gene clusters relative to each other; (ii) the arrangement of the terminal sequences involved in packaging of the viral genome; and (iii) the presence and distribution of nucleotides that are subject to methylation [202-208]. Fortuitously, most herpesviruses assigned to the three subfamilies would have been assigned to these subfamilies by most of the objective criteria. There are two major exceptions. The first is Marek's disease herpesviruses which share biological properties with members of the gammaherpesvirinae but would end up with alphaherpesvirinae on the basis of conservation and colinearity of gene clusters [209]. HHV6 is another example of a virus which should be classified with betaherpesvirinae on the basis of colinearity of gene clusters with those of human cytomegalovirus even though it shares important biologic properties with members of gammaherpesvirinae. The correlation between the biologic and molecular criteria which can be applied today to produce a similar clustering of viruses into subfamilies is gratifying but not necessarily reassuring. The quandary associated with the classification of Marek's disease viruses and of human herpesvirus No. 6 are portents of problems yet to come. The alpha, beta and gammaherpesvirinae differ from each other in fundamental biological properties and the objective criteria that should be used to describe them should reflect these properties. In the case of Marek's disease virus, the genes conserved and colinear with those of varicella-zoster virus [209] are not the domains expressed during latency or in transformed cells [145]. The key issue is the value that should be assigned to the conservation of genes and colinearity of gene clusters rather than to the evolution of novel, non-conserved genes which define biologic behavior. Delineation and evolutionary relatedness of genes responsible for biologic properties may be a more significant criterion for both evolutionary relatedness and classification than the arrangement and evolution of genes conserved throughout the family herpesviridae, but these are not yet known. THE RELATION BETWEEN HUMAN AND ANIMAL HERPESVIRUSES The currently known herpesviruses listed in Table 1 very likely represent a very small fraction of the total herpesviruses infecting eukaryotic organisms. Some of the viruses

72

BERNARD ROIZMAN and JOEL BAINES

listed in Table 1 m a y turn out to be herpesviruses o f other species and not truly endogenous to the species from which they have been isolated. Nevertheless, the recent discovery o f two new h u m a n herpesviruses, i.e. h u m a n herpesviruses 6 and 7 [15, 16] suggests that m a n y m o r e herpesviruses will be discovered from animals o f economic importance and, eventually, from wildlife as well. The significant aspects o f the list are that (i) members o f all viral subfamilies are endogenous to and infect h u m a n s and (ii) related viruses have been f o u n d in animal species. The herpesviruses infecting experimental animals are i m p o r t a n t models o f herpesvirus pathogenicity since m a n y aspects o f pathogenic manifestations in h u m a n s are also seen in animals infected with endogenous herpesviruses. Conversely, the lessons learned from studies on the effects of antivirai drugs and antiviral immunity in h u m a n s has its application in animals. N o t w i t h s t a n d i n g the relatedness o f herpesviruses comprising genera and subfamilies, crossing o f species barriers by these viruses is rare. A l t h o u g h several alphaherpesviruses occasionally infect species other than the natural host, the clinical picture is often markedly different in the new species. Thus, h u m a n herpes simplex viruses m a y cause severe disseminated infections in certain primate species and herpes B virus m a y cause severe disease in humans. Similarly, while infection o f adult swine with pseudorabies virus usually produces only mild disease, infection o f cattle, goats or dogs is often fatal. While infections o f unnatural n o n - h u m a n hosts are economically important, they are not epidemiologically significant since they rarely contribute to viral persistence in nature. In contrast to infection o f unnatural hosts, infection of i m m u n o c o m p e t e n t natural hosts seldom presents severe disease. The evolution o f exquisite and diverse mechanisms for the establishment and maintenance o f latency and the reduced capacity o f herpesviruses to causes severe disease in their natural hosts as c o m p a r e d to heterologous hosts suggests that herpesviruses have evolved a relationship with their hosts that permits them to survive and be perpetuated. Because o f their diversity, each herpesvirus, whether h u m a n or animal, presents a unique challenge and herpesviruses will remain objects o f study for m a n y years to come. REFERENCES 1. Gruter W. Das Herpesvirus, seine aetiologische und klinische Bedeutung. Miinch. reed. Wschr. 71, 1058-1060 (1924). 2. McGeoch D. J., Dalrymple M. A., Davison A. J., Dolan A., Frame M. C., McNab D., Perry L. J., Scott J. E. and Taylor P. The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1. J. gen. Virol. 69, 1531-1574 (1988). 3. Roizman B. and Sears A. E. Herpes simplex viruses and their replication. In Fields" Virology, 2nd edn (Edited by Fields B. N., Knipe D. M., Chanock R. M., Hirsch M. S., Melnick J. L., Monath T. P. and Roizman B.), pp. 1795-1894. Raven Press, New York (1990). 4. SchneweisK. E. Serologische Untersuchungen zur Typendifferenzierungdes herpesvirus hominis, Z. Immun. Forsch. exp Ther. 12,4, 24-48 (1962). 5. Weller T. H. Serial propagation in vitro of agents producing inclusion bodies derived from varicella and herpes zoster. Proc. Soc. exp. Biol. Med. 83, 3440-3446 (1953). 6. Davison A. J. and Scott J. E. The complete DNA sequence of varicella-zoster virus. J. gen. Virol. 67, 1759-1816 (1986). 7. Gelb L. D. Varicella-zoster virus. In Fields" Virology, 2nd edn (Edited by Fields B. N. and Knipe D. M.), Vol. 2, pp. 2011-2054. Raven Press, New York (1990). 8. Epstein M. A., Henle W., Achong B. G. and Barr Y. M. Morphological and biological studies on virus in cultured lymphoblasts from Burkitt's lymphoma. J. exp. Med. 121, 761-770 (1965). 9. Baer R., Bankier A. T., Biggin M. D., Deininger P. L., Farrell P. J., Gibson T. G., HatfuU G., Hudson G. S., Satchwell S. C., Seguin C., Tuffnell P. S. and Barrell B. G. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature (Lond.) 310, 207-211 (1984).

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125. Osterhaus A. D. M. E., Yang H., Spijkers H. E. M., Groen J., Teppema J. S. and Van Steenis G. The isolation and partial characterization of a highly pathogenic herpesvirus from the harbor seal (Phoca vitulina). Archs Virol. 86, 239-251 (1985). 126. Borst G. H. A., Walvoort H. C., Reijnders P. J. H., Van der Kamp J. S. and Osterhaus A. D. M. E. An outbreak of a herpesvirus infection in harbor seals (Phoca vitulina). J. Wildl. Dis. 22. 1-6 (1986). 127. Diosi P., Babusceac L. and David C. Recovery of cytomegalovirus from the submaxillary glands of ground squirrels. Arch. ges. Virusforsch. 20, 383-386 (1967). 128. Barahona H. H., Daniel M. D., Katz S. L., Ingalis J. K., Melendez L. V. and King N. W. Isolation and in vitro characterization of a herpesvirus from ground squirrels (Citellus sp.). Lab. Anita. Sci. 25, 725-739 (1975). 129. Diosi P., Plavosin L., Arcan P. and David C. Recovery of a new herpesvirus from the ground squirrel. Path. Microbiol. 42, 42-48. 130. Ben-Porat T. and Kaplan A. S. Molecular biology of pseudorabies virus. In The Herpesviruses (Edited by Roizman B.), Vol. 3, pp. 105-173. Plenum Press, New York (1985). 131. Pensaert M. B. and Kluge J. P. Pseudorabies virus (Aujeszkys disease). In Virus Infections of Porcines (Edited by Pensaert M. B. and Horzinek M. C.). pp. 39--64. Elsevier, New York (1989). 132. L'Ecuyer C. and Corner A. H. Propagation of porcine cytomegalic inclusion disease virus in cell cultures: preliminary report. Can. J. cornp. Med. vet. Sci. 30, 321-326 (1966). 133. Valicek L., Smid B., Pleva V. and Mensik J. Porcine cytomegalic inclusion disease virus. Arch. ges. Virusforsch. 32, 19-30 (1970). 134. Baudet A. E. T. F. Mortality in ducks in the The Nederlands caused by a filterable virus: fowl plague. Tijdschr. Diergeneesk. 50, 455-459 (1928). 135. Breese Jr S. S. and Dardiri A. H. Electron microscopic characterization of duck plague virus. Virology 34, 160-169 (1968). 136. Docherty D. E., Romaine R. I. and Knight R. L. Isolation ofa herpesvirus from a bald eagle nesting. Avian Dis. 27, 1162-1165 (1983). 137. Kaleta E. F., Mikami T., Marschall H. J., Heffels U., Heidenreich M. and Stiburek B. A new herpesvirus isolated from black storks (Ciconia nigra). Avian Pathol. 9, 301 310 (1980). 138. Cornwell H. J. C., Wright N. G., and McCuster H. B. Herpesvirus infection of pigeons. II Experimental infection of pigeons and chicks. J. comp. Pathol. 80, 229-232 (1970). 139. Lee L. F., Armstrong R. L. and Nazerian K. Comparative studies of six avian herpesviruses. Avian Dis. 16, 799-805 (1972). 140. Mare C. J. and Graham D. L. Falcon herpesvirus, the etiologic agent of inclusion body disease of falcons. Infect. lmmun. 8, 118-126 (1973). 141. Cruickshank J. O., Berry D. M. and Hay B. The fine structure of infectious laryngotracheitis virus. J. Virol. 20, 376-378 (1963). 142. May H. G. and Tittsler R. P. Tracheo-laryngitis in poultry. J. Am. vet. reed. Ass. 67, 229-231 (1925). 143. Churchill A. E. and Biggs P. M. Agent of Marek's disease in tissue culture. Nature 215, 528-530 (1967). 144. Cebrian J., Kaschka-Dierich C., Berthelot N. and Sheldrick P. Inverted repeat nucleotide sequences in the genomes of Marek's disease virus and the herpesvirus of the turkey. Proc. natn. Acad. Sci. 79, 555 558 (1982). 145. Sugaya K., Bradley G., Nonoyama M. and Tanaka A. Latent transcripts of Marek's disease virus are clustered in the short and long repeat regions. J. Virol. 64, 5773-5782 (1990). 146. Fukuchi K., Sudo M., Lee Y.-S., Tanaka A. and Nonoyama M. Structure of Marek's disease DNA: detailed restriction enzyme map. J. Virol. 58, 102-109 (1984). 147. Bulow V. V. and Biggs P. M. Differentiation between strains of Marek's disease virus and turkey herpesvirus by immuno-fluorescence assays. Avian Pathol. 4, 133-145 (1975). 148. Shat K. A. and Calneck B. W. Characterization of an apparently nononcogenic Marek's disease virus. J. natn. Cancer Inst. 60, 1075 1082 (1978). 149. Burtscher H. and Grunberg W. Herpesvirus-hepatitis bei kranchen (Aves-Gruidae). I. Pathomorphologische Befunde. Zentbl. Vet Reihe B 26, 561-569 (1979). 150. Kawamura H., King D. J. and Anderson D. P. A herpesvirus isolated from kidney cell culture of normal turkeys. Avian Dis. 13, 853-863 (1969). 151. Kaleta E. F., Marschall H. J., Glunder G. and Stiburek B. Isolation and serological differentiation of a herpesvirus from bobwhite quail (Colinus virginianus, L. 1758). Archs Virol. 66, 359-364 (1980). 152. French E. L., Purchase H. G. and Nazerian K. A new herpesvirus isolated from a nestling cormorant (Phalacrocorax melanoleucos). Avian Pathol. 2, 3-15 (1973). 153. Simpson C. F., Hanley J. E. and Gaskin J. M. Psittacine herpesvirus infection resembling Pacheco's parrot disease. J. infect. Dis. 13, 390-396 (1975). 154. Kincaid A. L., Bunton T. E. and Cranfield M. Herpes-like infection in black-footed penguins (Spheniscus dermersus). J. Wildl. Dis. 24, 173-175 (1988).

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155. Schetter C. H. In vitro Untersuchungen uber die Eigenschaften des Virus der Hepatitis et Splenitis Infectiosa Strigum. Verhandlungsbericht X I I Int. Symp. Erkr. Zootiere, pp. 205-209. Budapest (1970). 156. Burki F., Burtscher H. and Sibalin M. Herpesvirus strigis: a new avian herpesvirus. I. Biological properties. Arch. ges. Virusforsch. 43, 14-24 (1973). 157. Hauser B., Mettler F. and Rubel A. Herpes-like infection in two young boas. J. comp. Path. 93, 515 519 (1983). 158. Rebell G., Rywlin A. and Haines H. A herpesvirus-type agent associated with skin lesions of green sea turtle in aquaculture. Am. J. vet. Res. 36, 1221 1224 (1975). 159. Haines H. and Kleese W. C. Effect of water temperatures on a herpesvirus infection of sea turtles. Infect. Immun. 15, 756-759 (1977). 160. Frye F. L., Oshiro L. O., Dutra F. R. and Carney J. D. Herpesvirus-like infection in two Pacific pond turtles. J. Am. vet. reed. Ass. 171, 882-884 (1977). 161. Cox W. R., Rapley W. A. and Barker I. K. Herpesvirus-like infection in the painted turtle (Chrysemyspicta). J. Wildl. Dis. 16, 445-449 (1980). 162. Jacobson E. R., Gaskin J. M. and Wahlquist H, Herpes-like infection in map turtles. Am. J. Vet. Res. 181, 1322 1324 (1982). 163. Jacobson E. R., Clubb S., Gaskin J. M. and Gardner C. Herpesvirus like infection in Argentine tortoises. J. Am. vet. med. Ass. 187, 1227-1229 (1985). 164. Monroe J. H., Shibley G. P., Schidlovsky G., Nakai T., Howalson A. F., Wivel N. W. and O'Connor T. E. Action of snake venom on Rauscher virus. J. natn. Cancer Inst. 40, 135 145 (1968). 165. Lunger P. D. and Clark H. F. Reptilia-related viruses. Adv. Virus Res. 23, 159 204 (1978). 166. Zeigel R. F. and Clark H. F. Electron microscopic observation on a new herpes-type virus isolated from Iguana iguana and propagated in reptilian cells in vitro. Infect. Immun. 5, 570 582 (1972). 167. Clark H. F. and Karzon D. T. Iguana virus, a herpes-like virus isolated from cultured cells of a lizard, Iguana iguana. Infect. Immun. 5, 559 569 (1972). 168. Raynaud A. and Adrian M. Lesions cutanees a structure papillomatouse associees a des virus chez le lezard vert (Lacerta virelis laur.). C.r. Acad. Sci. Set. D. 283, 845 847 (1970). 169. Lucke B. Carcinoma of the leopard frog: its probable causation by a virus. J. exp. Med. 68, 457 466 (1938). 170. Wagner E. K., Roizman B., Savage T., Spear P. G., Mizell M., Durr F. E. and Sypowicz D. Characterization of the D N A of herpesviruses associated with Lucke adenocarcinoma of the frog and Burkitt lymphoma of man. Virology 42, 257 261 (1970). 171. Gravell M. Viruses and renal carcinoma of Rana pipiens. X. Comparison of herpes type viruses associated with Lucke tumor-bearing frogs. Virology 43, 730-733 (1971). 172. Rafferty K. A. The cultivation of inclusion-associated virus from Lucke tumor frogs. Ann. N. Y. Acad. Sci. 126, 3-21 (1965). 173. Schubert von G. Electronenmikroskopische Untersuchungen zur Pockenkrankheit des Karpfens. Z. Natur/~ 19, 675 682 (1964). 174. Yamamoto T., Kelly R. K. and Nielson O. Epidermal hyperplasias of Northern pike (Esox lucius) associated with herpesvirus and C-type particles. Archs Virol. 79, 255 272 (1983). 175. Wolf K. and Darlington R. W. Channel catfish virus: a new herpesvirus of ictalurid fish. J. Virol. 8, 525-533 (1971). 176. Chousterman S., Lacasa M. and Sheldrick P. Physical map of the channel catfish virus genome: location of sites for restriction endonucleases EcoRI, HindlII, Hpal, and XbaI. J. Virol. 31, 73 85 (1979). 177. Kelly R. K., Nielson O. and Yamamoto T. A new herpes-like virus (HLV) of fish (Stizostedion vitreum-vitreum): Abstract, Proceedings of the Meeting of the Tissue Culture Association. In Vitro 16, 225 (1980). 178. Buchanan J. S., Richards R. H., Sommerville C. and Madeley C. R. A herpestype virus from turbot (Scophthalamus maximus L.). Vet. Rec. 102, 527 528 (1978). 179. Wolf K., Darlington R. W., Taylor W. G., Quimby M. C. and Nagabayashi T. Herpesvirus salmonis: characteristics of a new pathogen of rainbow trout. J. Virol. 27, 659-666 (1978). 180. Kimura T., Ioshimizu M. and Tanaka M. Salmonid viruses: effect of Oncorhynchus mason virus (OMV) in fry of chum salmon (Oncorhynchus keta). Fish Hlth News 9, 2-3 (1980). 181. Furlong D., Swift H. and Roizman B. Arrangement of herpesvirus deoxyribonucleic acid in the core. J. Virol. 10, 1071-1074 (1972). 182. Nazerian K. DNA configuration in the core of Marek's disease virus. J. Virol. 13, 1148-1150 (1974). 183. Wildy P. and Watson D. H. Electron microscopic studies on the architecture of animal viruses. Cold Spring Harbour Syrup. Quant. Biol. 27, 25 47 (1963). 184. Roizman B. and Furlong D. The replication of herpes-viruses. In Comprehensive Virology (Edited by Fraenkel-Conrat H. and Wagner R. R.), Vol. 3, pp. 229 403. Plenum Press, New York (1974). 185. Morgan C., Rose H. M. and Mednis B. Electron microscopy of herpes simplex virus. I. Entry. J. Virol. 2, 507-516 (1968).

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186. Morgan C., Rose H. M., Holden M. and Jones E. P. Electron microscopic observations on the development of herpes simplex virus. J. exp. Med. 110, 643-656 (1959). 187. Fong C. K. Y., Tenser R. B., Hsiung G. D. and Gross P. A. Ultrastructural studies of the envelopment and release of guinea pig herpeslike virus in cultured cells. Virology 52, 468-477 (1973). 188. McCombs R., Brunschwig J. P., Mirkovic R. and Benyesh-Melnick M. Electron microscopic characterization of a herpes-like virus isolated from tree shrews. Virology 45, 816-820 (1971). 189. Epstein M. A. Observations on the fine structure of mature herpes simplex virus and on the composition of its nucleoid. J. exp. Meal. 115, 1-12 (1962). 190. Armstrong J. A., Pereira H. G. and Andrewes C. H. Observations of the virus of infectious bovine rhinotracheitis and its affinity with the herpesvirus group. Virology 14, 276-285 (1961). 191. Falke D., Siegert R. and Vogell W. 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E. G., Ross N. L. J. and Binns M. M. Gene sequence and mapping data from Marek's disease virus and herpesvirus of turkeys: implications for herpesvirus classification. J. gen. Virol. 69, 2033-2042 (1988).