MRC Virology Unit, Institute of Virology, Glasgow, UK Introduction Members of the family Herpesviridae replicate their genomes in the infected cell nucleus and have a characteristic virion morphology, which consists of the envelope, tegument, capsid and core Davison and Clements, The present chapter focuses on the viral genome, which occupies the core of the virus particle. Electron microscopy of negatively stained capsids gives the impression that the core consists of the viral DNA molecule wrapped toroidally around a protein spindle Furlong et al. Images reconstructed from electron micrographs of virions frozen in ice in the absence of stain, a technique by which morphology is better preserved, show that the core consists of the DNA packed at high density in liquid crystalline form, probably as a spool lacking a spindle Booy et al. The genome termini are not covalently closed as in the Poxviridae; Moss, or covalently linked to a protein as in the Adenoviridae; Shenk,
|Published (Last):||25 November 2016|
|PDF File Size:||5.64 Mb|
|ePub File Size:||3.54 Mb|
|Price:||Free* [*Free Regsitration Required]|
MRC Virology Unit, Institute of Virology, Glasgow, UK Introduction Members of the family Herpesviridae replicate their genomes in the infected cell nucleus and have a characteristic virion morphology, which consists of the envelope, tegument, capsid and core Davison and Clements, The present chapter focuses on the viral genome, which occupies the core of the virus particle.
Electron microscopy of negatively stained capsids gives the impression that the core consists of the viral DNA molecule wrapped toroidally around a protein spindle Furlong et al. Images reconstructed from electron micrographs of virions frozen in ice in the absence of stain, a technique by which morphology is better preserved, show that the core consists of the DNA packed at high density in liquid crystalline form, probably as a spool lacking a spindle Booy et al.
The genome termini are not covalently closed as in the Poxviridae; Moss, or covalently linked to a protein as in the Adenoviridae; Shenk, Larger herpesvirus genomes are accommodated in larger capsids, but the relationship is not proportional, as the packing density of the DNA varies somewhat between species Trus et al.
The reasons for the striking range in nucleotide composition of herpesvirus genomes are not clear, but a similar phenomenon is found in other virus families and in cellular organisms. In vertebrate genomes, this phenomenon is thought to be due to spontaneous deamination of 5-methylcytosine residues in DNA to thymidine residues, followed by fixation through DNA replication. CG depletion in herpesviruses, and concomitant enrichment in TG and CA, has been taken as indicative of latency in dividing cell populations, in which the latent genome is obliged to replicate as host cells divide Honess et al.
Thus, HSV-1, which is resident in non-dividing neurons, has a CG content consistent with its nucleotide composition, whereas EBV, which latently infects dividing B cell populations, is depleted. Sequenced herpesvirus genomes. Genome structures Herpesvirus genomes are not simple lengths of unique DNA, but characteristically contain direct or inverted repeats. The reasons for this are not known, but it is intriguing that similar structures appear to have arisen independently on several occasions during herpesvirus evolution.
Herpesvirus genomes are thought to replicate by circularization, followed by production of concatemers and cleavage of unit-length genomes during packaging into capsids Boehmer and Lehman, The explanation for the presence of repeats is probably connected in some way with the mode of DNA replication, rather than with any advantage gained by having multiple copies of certain genes.
Although greater expression would be a consequence of repeated genes, this appears a simplistic explanation in an evolutionary context, since subtler processes of nucleotide substitution can readily alter transcriptional levels over a much greater range. In addition, repeats often do not contain protein-coding regions. As elaborated below, certain genomes exhibit a further structural complexity known as segment inversion, in which unique regions flanked by inverted repeats are found in both orientations in virion DNA.
Thus, a genome with two such unique regions would produce either two or four isomers depending on whether one or both regions invert. This phenomenon is probably a consequence of recombination between repeats in concatemeric DNA. Isomers are functionally equivalent Jenkins and Roizman, , and segment inversion appears to be unrelated to the biology of the virus.
The class A genome consists of a unique sequence flanked by a direct repeat. It was first described for CCV Chousterman et al. In these examples, the direct repeat is several kbp in size. Other members of the Betaherpesvirinae also have this arrangement, but the repeat is smaller, at bp in RCMV Vink et al. Unique and repeat regions are shown as horizontal lines and rectangles, respectively.
The orientations of repeats are shown by arrows. The nomenclature of more Class B genomes also have directly repeated sequences at the termini, but these consist of variable copy numbers of a tandemly repeated sequence of 0.
The presence of additional terminal repeat sequences in inverse orientation internally in the genome gives rise to a related structure, which is present in another member of the Gammaherpesvirinae, cottontail rabbit herpesvirus Cebrian et al. The virion DNA of this virus exhibits segment inversion because the two unique regions are flanked by inverted repeats.
The class C structure represents another derivative of class B, in which an internal set of direct repeats is present but is unrelated to the terminal set. Segment inversion does not occur because the internal and terminal repeats are not related. Segment inversion occurs inasmuch as equimolar amounts of genomes containing the two orientations of US are found in virion DNA, but UL is present predominantly or completely in one orientation.
Class E is the most complex genome structure, and was the first to be described, for HSV-1 Sheldrick and Berthelot, Also, class E genomes are terminally redundant, containing a sequence of a few hundred bp termed the a sequence that is repeated directly at the genome termini and inversely at the IRL-IRS junction Sheldrick and Berthelot, ; Grafstrom et al.
A structure similar to both class D and E genomes has also evolved in an invertebrate herpesvirus, OsHV-1 Davison et al. This contains two segments, each consisting of a unique region flanked by an substantial inverted repeat, linked via an additional small, non-inverting unique region. As in class E genomes, the two segments undergo inversion, but, like class D, the genome is not terminally redundant. Class F is represented by a member of the Betaherpesvirinae, THV, which apparently lacks the types of inverted and direct repeats that characterize other herpesvirus genomes Koch et al.
However, since the genome ends of THV have not been analyzed directly, the existence of this unusual structure is considered tentative. Additional strains have been sequenced for some species, yielding a total of 63 sequenced strains. The ease of generating data will continue to expand the number of herpesvirus species and strains sequenced in coming years. Indeed, substantial inroads have been made into large-scale studies of strain variation for certain of the human herpesviruses.
It appears that the scale and extent of variation is lineage dependent, with Betaherpesvirinae more variable than Gammaherpesvirinae, and Alphaherpesvirinae the least variable Murphy et al. The development of tools to study variation in increasing detail will enhance understanding of viral epidemiology, in terms both of its relation to human evolution and migration and of the changes that are occurring in human populations at the present time.
Gene content Sequencing herpesvirus genomes is now routine, but the process of describing gene content annotation is not trivial. Thus, as with other groups of organisms, the quality of annotation of herpesvirus entries in the public databases varies widely.
It is an unfortunate fact that no set of objective criteria is sufficient to interpret the gene content of a sequence completely. Although most genes can be catalogued relatively easily, there are genuine difficulties in identifying all of them, even in the best characterized herpesviruses.
A primary criterion in defining gene content involves identifying open reading frames ORFs , usually those initiated by methionine ATG codons. A tendency to include ORFs that do not encode proteins may be reduced by setting a minimum size.
Comparative genomics, which operates on the principle that genes are conserved in evolution, and algorithms that compare sequence patterns within ORFs to the protein-coding regions of known genes, are also useful. However, these tools yield results with least confidence when applied to small, spliced, overlapping or poorly conserved ORFs, and in instances where translation initiates from internal codons, alternative splicing occurs, or esoteric translational mechanisms are employed e.
In addition to sequence analysis, experimental data on production of an RNA or protein from an ORF provides important imput, although even this falls short of proving functionality. Also, most approaches are aimed at identifying protein-coding genes, and cannot detect genes that encode functional transcripts that are not mRNAs.
The use of different criteria for gene identification may create a degree of uncertainty and debate, and lead to different pictures of gene layout. The case of HCMV provides a contemporary example. Later, the gene number was reduced to by comparing the HCMV and CCMV genomes, allowing, where appropriate, for the presence of genes unique to either genome Davison et al.
As modified criteria were applied, this number rebounded in a series of increments, first to Yu et al. Although the conservative numbers in this example are more supportable, the existence of unrecognized genes should not be ruled out even in well-characterized genomes, and candidates should be examined rigorously. For example, new genes were identified in previously analysed sequences for VZV Kemble et al.
Some of the immediate early proteins regulate expression of early and late genes Honess and Roizman, Early genes, defined as those expressed in the presence of immediate early proteins and before the onset of DNA replication, include enzymes involved in nucleotide metabolism and DNA replication and a number of envelope glycoproteins.
Although the details differ, a similar pattern of regulated gene expression is characteristic of all herpesviruses examined; for example, HCMV Stinski, , HHV-8 Sarid et al. In addition, herpesviruses express RNAs whose functions apparently do not involve translation. Apart from families of duplicated genes, there is no pronounced clustering of genes on the basis of function or kinetics of expression. Most splicing involves genes that are relatively recent evolutionary developments, and Beta- and Gammaherpesvirinae have more spliced genes than Alphaherpesvirinae.
In this section, an overview is given of genetic relatedness at selected levels in the phylogenetic tree, starting with the three major groups that encompass all known herpesviruses, proceeding to the best characterized of these groups, and ending with one subfamily in this group. In chronological terms, this proceeds from earlier to more recent evolutionary events.
Detailed information on the gene content of, and the relationships between, the human herpesviruses is available elsewhere in this book. Three major groups Three major groups of viruses possess the herpesvirus morphology, including closely similar capsid structures, but share very little genetic similarity Davison, ; Booy et al.
Viruses in the best characterized group infect mammals, birds and reptiles, viruses in the second group infect amphibians and fish, and the third group contains the single known herpesvirus of an invertebrate, the oyster. Currently, the family Herpesviridae comprises the first group classified into three subfamilies and component genera, one member CCV of the second group representing an unassigned genus, and the oyster virus is a floating species.
The most logical means of accommodating all known herpesviruses taxonomically would be to establish three families under the umbrella of a new order Herpesvirales , containing herpesviruses of mammals, birds and reptiles, of amphibians and fish, and of bivalves, respectively.
Since these taxa are presently a proposal and lack any formal standing, the terms mammalian, fish and bivalve herpesvirus groups are used to denote the proposed families in the following discussion. Only three genes have clear counterparts in all three groups that are detectable by amino acid sequence comparisons. The proteins encoded by two DNA polymerase and dUTPase have ubiquitous cellular relatives and could have been captured independently from the host repertoire.
The third gene apparently lacks a counterpart in the host cell but has distant relatives in T4 and similar bacteriophages Davison, ; Mitchell et al. The existence of groups of viruses that exhibit close morphological similarities but generally lack detectable genetic relationships is not unique to the herpesviruses, and may be explained as the result either of convergence from distinct evolutionary sources or as divergence from an ancestor so ancient that sequence similarities have been obliterated.
The latter hypothesis is currently favored, but the existence of a common ancestor of all herpesviruses and any contingent dates for divergence of the groups must be viewed cautiously. More speculatively, apparent similarities in aspects of DNA packaging Booy et al. Phylogenetic analyses strongly support the view that herpesviruses have largely co-evolved with their hosts, often co-speciating with them. As would be expected of evolutionary phenomena, a number of problematic observations and exceptions have emerged as data have multiplied, especially in relation to early divergences.
From comparisons between the phylogenies of the viruses and their hosts, McGeoch and Cook proposed an evolutionary timescale for the Alphaherpesvirinae in which the Simplex- and Varicellovirus genera diverged about 73 million years ago, roughly coincident with the period of the mammalian radiation.
Even at this stage, potential exceptions to the co-evolution model were apparent. For example, the taxonomical position of avian herpesviruses among the Alphaherpesvirinae did not fit well, and prompted the suggestion of ancient interspecies transfers between mammals and birds. In this scheme, a similar argument may be necessary to explain the position of reptilian turtle herpesviruses in the same subfamily Quackenbush et al.
Assuming the constancy of the molecular clock derived for the Alphaherpesvirinae, McGeoch et al. Given the contrasting lack of relationships between the groups and substantial relationships within them see below , this date did not fit well qualitatively with a model in which the fish and mammalian herpesvirus groups co-speciated when teleosts separated from other vertebrates. In a recent analysis utilizing improved algorithms and the latest estimates for host divergence dates, McGeoch and Gatherer pushed back the common ancestor of the Alpha-, Beta- and Gammaherpesvirinae to about million years ago, which permitted a greater degree of support for co-evolution of the Alphaherpesvirinae, including avian and reptilian members.
In this scheme, a much earlier, non-co-speciative divergence may be indicated for the mammalian and fish herpesvirus groups along with one of similar or greater antiquity for the bivalve herpesvirus group. However, this would lack the advantage of explaining the segregation of the viral groups to distinct parts of the animal kingdom and necessitate additional arguments involving viral extinction.
The mammalian herpesvirus group In contrast to the lack of extensive relationships between the three groups, members of the mammalian herpesvirus group are clearly related to each other Davison, , as are those in the fish herpesvirus group Bernard and Mercier, ; Davison, ; Davison et al. This number assumes a small degree of approximation, since amino acid sequence conservation among the set varies from substantial to marginal.
The core genes are shaded grey in Fig. Accumulation of more recently evolved genes near the termini is a feature of linear, double-stranded DNA genomes from other virus families, such as the Poxviridae Upton et al.
The core genes are ordered similarly in the same subfamily, except for certain members of the Alphaherpesvirinae in which different arrangements are apparent: PRV in the Varicellovirus genus Ben-Porat et al. However, as shown in Fig.
Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.
Table In the USA, a decline in varicella incidence has also been documented from passive surveillance systems. At the national level, significant declines in varicella mortality, and in varicella-related hospitalizations and their attendant costs have been also been documented in the United States Nguyen et al. Routine childhood vaccination programs are the most effective strategy for interrupting disease transmission and reducing varicella mortality and morbidity in both temperate and tropical climates. Achieving high vaccination coverage among children will provide the additional benefits of herd immunity with protection of susceptible adults, infants and other persons at high risk for severe varicella disease who are not eligible for vaccination.
Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis
MRC Virology Unit, Institute of Virology, Glasgow, UK Introduction Taxonomy aims to structure relationships among diverse organisms in order to provide a broader understanding of Nature than is afforded by consideration of organisms in isolation. Since biological systems are shaped by evolution, which is not influenced by the human desire to impose order, any taxonomical scheme is bound to be incomplete and to some extent arbitrary. The criteria applied are necessarily confined to what is technically possible, and thus taxonomy has an important historical component. In addition, taxonomy develops conservatively, since striving for the ideal must be tempered by the need to maintain utility. It is also an unfortunate fact that taxonomy provides fertile soil for debate among a few but is of little interest to most. However, it is beyond dispute that the setting of herpesviruses in a taxonomical framework is vital for understanding the origins and behavior of this fascinating family of organisms.