Viral modulation of NK cell immunity

Natural killer (NK) cells have been implicated in innate immune responses against viruses such as herpesviruses, which cause persistent infections in the host. In response to the selective pressure that is exerted by NK cells, many viruses have evolved strategies either to evade detection by NK cells or to modulate the activity of NK cells. Here, we review the unique relationship that exists between NK cells and viruses, with a focus on herpesviruses.     

BHV-1: new molecular approaches to control a common and widespread infection.

BACKGROUND: Herpesviruses are widespread viruses, causing severe infections in both humans and animals. Eradication of herpesviruses is extremely difficult because of their ability to establish latent and life-long infections. However, latency is only one tool that has evolved in herpesviruses to successfully infect their hosts; such viruses display a wide (and still incompletely known) panoply of genes and proteins that are able to counteract immune responses of their hosts. Envelope glycoproteins and cytokine inhibitors are two examples of such weapons. All of these factors make it difficult to develop diagnostics and vaccines, unless they are based on molecular techniques. MATERIALS AND METHODS: Animal herpesviruses, because of their striking similarity to human ones, are suitable models to study the molecular biology of herpesviruses and develop strategies aimed at designing neurotropic live vectors for gene therapy as well as engineered attenuated vaccines. RESULTS: BHV-1 is a neurotropic herpesvirus causing infectious rhinotracheitis (IBR) in cattle. It is a major plague in zootechnics and commercial trade, because of its ability to spread through asymptomatic carrier animals, frozen semen, and embryos. Such portals of infections are also important for human herpesviruses, which mainly cause systemic, eye, and genital tract infections, leading even to the development of cancer. CONCLUSIONS: This review covers both the genetics and molecular biology of BHV-1 and its related herpesviruses. Epidemiology and diagnostic approaches to herpesvirus infections are presented. The role of herpesviruses in gene therapy and a broad introduction to classic and engineered vaccines against herpesviruses are also provided. http://link.springer-ny. com/link/service/journals/00020/bibs/5n5p261.html     

Regulation of Herpesvirus Reactivation by Host MicroRNAs

The interplay between latent and lytic modes of infection is central to successful infection of all herpesviruses, yet knowledge of the determinants that govern reactivation of these viruses from latent to lytic infection is limited. Recently, several studies have identified roles for specific cellular microRNAs in inhibiting reactivation of various herpesviruses, thereby promoting latent infections. These studies are discussed in the context of current knowledge on mechanisms of regulation of reactivation of specific herpesviruses.     

The outbreak of carp disease caused by CyHV-3 as a model for new emerging viral diseases in aquaculture: a review

Aquacultured koi and common carp (Cyprinus carpio) are intensively bred for ornamental purposes and for human consumption worldwide. The carp and koi farming industries have suffered enormous economic losses over the past decade due to an epizootic disease caused by Cyprinus herpesvirus-3 (CyHV-3) also known as koi herpesvirus and carp interstitial nephritis gill necrosis virus. CyHV-3 is a large dsDNA virus, morphologically similar to herpesviruses, yet contains genetic elements similar to those of pox, irido- and herpesviruses. Considering the phylogenic distance between CyHV-3 and higher vertebrate herpesviruses, CyHV-3 represents the prototype of viruses assigned to the novel family Alloherpesviridae. Although emergence of a new virus rarely initiates a pandemic so severe that it reduces the life expectancy of a population, CyHV-3 is exceptional because of its enormous impact on the world carp population. High population density is the major contributing factor to the epizootic disease caused by CyHV-3.     

Poly I:C inhibits the expression of channel catfish virus immediate-early gene ORF 1 at early times after infection

Channel catfish virus (CCV) is a herpesvirus that infects channel catfish fry and fingerlings. Previous research has demonstrated that Type I interferons inhibit the expression of immediate-early (IE) genes of some mammalian herpesviruses. However, CCV is distantly related to the mammalian herpesviruses and Type I interferons from higher vertebrates exhibit only 20% similarity to fish interferons. In this work we demonstrate that treatment of channel catfish ovary (CCO) cells, a fibroblast-like cell line, with poly I:C, a known inducer of Type I interferons, results in inhibition of expression of the CCV IE gene ORF 1. Thus, although the genes involved have diverged, the mechanism appears to be conserved. If this paradigm holds true for other CCV IE-Type I interferon interactions, it could have important implications for the impact of CCV on the host immune system.     

The Genome of Salmonid Herpesvirus 1

Salmonid herpesvirus 1 (SalHV-1) is a pathogen of the rainbow trout (Oncorhynchus mykiss). Restriction endonuclease mapping, cosmid cloning, DNA hybridization, and targeted DNA sequencing experiments showed that the genome is 174.4 kbp in size, consisting of a long unique region (U_L; 133.4 kbp) linked to a short unique region (U_S; 25.6 kbp) which is flanked by an inverted repeat (R_S; 7.7 kbp). U_S is present in virion DNA in either orientation, but U_L is present in a single orientation. This structure is characteristic of the Varicellovirus genus of the subfamily Alphaherpesvirinae but has evidently evolved independently, since an analysis of randomly sampled DNA sequence data showed that SalHV-1 shares at least 18 genes with channel catfish virus (CCV), a fish herpesvirus whose complete sequence is known and which is unrelated to mammalian herpesviruses. The use of oligonucleotide probes demonstrated that in comparison with CCV, the conserved SalHV-1 genes are located in U_L in at least five rearranged blocks. Large-scale gene rearrangements of this type are also characteristic of the three mammalian herpesvirus subfamilies. The junction between two SalHV-1 gene blocks was confirmed by sequencing a 4,245-bp region which contains the dUTPase gene, part of a putative spliced DNA polymerase gene, and one other complete gene. The implications of these findings in herpesvirus taxonomy are discussed.Herpesviruses are a large group of complex, double-stranded DNA viruses which infect vertebrates from teleost (bony) fish to humans. They exhibit narrow host specificites, most infecting only a single species in nature, and are thus considered likely to have evolved with their hosts. Comparisons of primary amino acid sequences predicted from complete genome sequences have shown that mammalian herpesviruses are genetically very divergent but nonetheless share a set of about 40 homologous genes, thus providing compelling evidence that these viruses evolved from a single ancestral herpesvirus (reviewed in reference 7). Moreover, genetic comparisons support the division of the family into three subfamilies, Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae, as proposed previously from biological criteria (15). The order of genes is largely conserved within each subfamily, whereas members of different subfamilies are more distantly related and exhibit several large-scale genomic rearrangements (4, 9). Viral phylogenies derived from rigorous sequence comparisons generally fit well with host phylogenies deduced from the fossil record, thus supporting the view that mammalian herpesviruses have cospeciated with their hosts, and this has allowed a time frame to be assigned (13, 14). Moreover, limited sequence data also indicate that avian herpesviruses fit readily into the subfamily Alphaherpesvirinae.Nearly all research on herpesviruses has involved mammalian (and, to a lesser extent, avian) herpesviruses, and little is known about the many herpesviruses which infect cold-blooded vertebrates. The most extensively studied member of the latter group, channel catfish virus (CCV; ictalurid herpesvirus 1), was initially classified as a herpesvirus on the basis of its virion morphology and as a member of the Alphaherpesvirinae on the basis of its biological properties (15). Analysis of the complete genome sequence (6) indicated, however, that CCV has no specific relationship with mammalian herpesviruses at the level of primary amino acid sequence, in that no counterpart of a protein which is encoded only by mammalian herpesviruses, such as a structural protein, was detected in CCV. Thus CCV cannot be accommodated by the current taxonomy. The virus does encode several enzymes which are also specified by mammalian herpesviruses, such as DNA polymerase, dUTPase, and thymidine kinase. The genes encoding these proteins, however, are ubiquitous and could quite possibly have been acquired independently by the mammalian and fish herpesvirus lineages. Moreover, the CCV enzymes are no more closely related to their counterparts in other herpesviruses than to those in other organisms.These findings may be interpreted in two ways. First, CCV and mammalian herpesviruses arose independently and have convergently acquired similar virion morphologies. Second, they evolved from an ancestral herpesvirus but have diverged so extensively over the 400 million years since their hosts separated that little sequence evidence remains. Several lines of evidence support the latter view, but it is fair to say that the case is not yet overwhelming. The best genetic indication for divergence rests in a single highly conserved protein which is encoded by two exons in the mammalian herpesviruses and three in CCV (open reading frames [ORFs] 62, 69, and 71). This protein apparently has a distant relative in bacteriophage T4 which functions as a subunit of the terminase involved in DNA packaging, but the fact that no cellular counterpart has yet been discovered highlights it as the best candidate for a gene which may have been inherited from a common ancestor rather than acquired via independent capture events. Moreover, despite the lack of conservation of the amino acid sequences of structural proteins, structural and functional congruences have been detected. Thus, the detailed three-dimensional structure of the CCV capsid is strikingly similar to that of herpes simplex virus type 1 (3). Also, local sequence features of the putative scaffold protein involved in CCV capsid formation suggest that it may be autoproteolytically processed via a pathway that is otherwise found only in mammalian herpesviruses (8).Evidence for a herpesvirus lineage that lies outside the current taxonomic scheme has prompted investigations of its extent. Comparisons of CCV with salmonid herpesviruses appear useful in this respect, since the fossil record indicates that the three main subgroups of euteleosts (salmoniforms, neoteleosts, and ostariophysans, the latter including catfish) diverged around 130 million years ago (1). Salmonid fish are host to several herpesviruses, the principal of which are salmonid herpesviruses 1 and 2 (SalHV-1 and SalHV-2) (reviewed in reference 19). SalHV-1 was isolated on several occasions from a rainbow trout (Oncorhynchus mykiss) hatchery in the state of Washington in association with excessive mortality in young fish (20). The virus causes disease when injected into young rainbow trout maintained at 6 to 9°C but not in other salmonid species. SalHV-2 was isolated from Oncorhynchus masou, a landlocked Japanese form of Pacific salmon (11). It is serologically distinct from and has a wider host range than SalHV-1, causing virulent disease in the young of several Oncorhynchus species, including the rainbow trout. It also exhibits a higher temperature optimum for growth in cell culture than SalHV-1.Partial sequence data for two genes have previously indicated that SalHV-2 is related to CCV (2). In this report, I describe the genome structure and gene arrangement of SalHV-1 and show that this virus is evolutionarily related to SalHV-2 and CCV. The data indicate that the processes which have resulted in the generation of certain genome structures and large-scale gene rearrangements during mammalian herpesvirus evolution have parallels in fish herpesvirus evolution. They also imply that fish herpesviruses occupy a distinct evolutionary space of an size equivalent to that occupied by mammalian herpesviruses and urge an accommodation in the herpesvirus taxonomy.     

Comparative transmission of multiple herpesviruses and simian virus 40 in a baboon breeding colony

Little is known about the natural history of herpesviruses indigenous in baboons. Here, we describe the development of ELISAs for five herpesviruses. These assays were used to test more than 950 serum samples collected from approximately 210 infant/juvenile and 130 adult baboons in a captive breeding colony over a period of seven years. Results indicated that baboon cytomegalovirus, lymphocryptovirus, and rhadinovirus are transmitted efficiently within the colony and are acquired at an early age. Baboon alpha-herpesvirus HVP2 and polyomavirus simian virus 40 (SV40) were acquired later and by fewer juveniles than were the other three herpesviruses. More than 60% of baboons acquired HVP2 before reaching sexual maturity, indicating that oral infection of infants and juveniles, rather than sexual transmission between adults, is the predominant mode of transmission for this virus. Antibody to simian varicella virus (SVV) was found in about 40% of baboons. SVV was acquired principally by infants and juveniles; few adults seroconverted despite seronegative adults being in constant contact with infants and juveniles undergoing primary infection. Time of seroconversion was not statistically correlated to specific individual herpesviruses, suggesting that each virus is acquired as an independent infection event rather than multiple viruses being acquired at the same time. Several baboons that were delivered by cesarean section and were housed separate from, but in close proximity to, other baboons remained free of many or all viruses for several years, suggesting that, similar to human herpesviruses, baboon herpesviruses and SV40 are transmitted principally by direct contact.     

The alloherpesviral counterparts of interleukin 10 in European eel and common carp

Viral interleukin 10 (IL-10) like open reading frames have been identified in several pox- and herpesviruses, including the fish herpesviruses Anguillid herpesvirus 1 (AngHV-1) and Cyprinid herpesvirus 3 (CyHV-3). European eel (Anguilla anguilla) IL-10 was sequenced, in order to compare European eel and common carp (Cyprinus carpio) IL-10 with their alloherpesviral counterparts. Homology between the virus and host IL-10 amino acid sequences is low, which is confirmed by phylogenetic analysis. However, the three dimensional structures of the fish and alloherpesviral IL-10 proteins as predicted by modeling are highly similar to human IL-10. Closely related AngHV-1 and CyHV-3 are expected to have obtained their viral IL-10 genes independently in the course of coexistence with their respective hosts. The presence and structural conservation of these alloherpesviral IL-10 genes suggest that they might play an important role in the evolution of pathogenesis.     

Antigenic comparisons between herpesviruses isolated from fallow deer in Alberta and the viruses of infectious bovine rhinotracheitis, equine rhinopneumonitis and DN-599, a non-IBR bovine herpesvirus.

Antigenic comparison studies of three herpesviruses isolated from fallow deer (Dama dama) in Alberta and herpesviruses from some domestic species were carried out by the alpha serum-virus neutralization test. Complete cross neutralization was demonstrated among the deer herpesviruses and equine herpesvirus type 1.     

Simian homologues of human herpesviruses and implications for novel viral introduction to free-living mountain gorillas

The endangered mountain gorilla (Gorilla beringei beringei) in Rwanda, Uganda, and the Democratic Republic of Congo is frequently in contact with humans through tourism, research activities, and illegal entry of people into protected gorilla habitat. Herpesviruses, which are ubiquitous in primates, have the potential to be shared in any setting where humans and gorillas share habitat. Based on serological findings and clinical observations of orofacial ulcerated lesions resembling herpetic lesions, an alpha-herpesvirus resembling human herpes simplex virus type 1 (HSV-1) has long been suspected to be present in human-habituated mountain gorillas in the wild. While the etiology of orofacial lesions in the wild has not been confirmed, HSV-1 has been suspected in captively-housed mountain gorillas and confirmed in a co-housed confiscated Grauer's gorilla (Gorilla beringei graueri). To better characterize herpesviruses infecting mountain gorillas and to determine the presence/absence of HSV-1 in the free-living population, we conducted a population-wide survey to test for the presence of orally shed herpesviruses. DNA was extracted from discarded chewed plants collected from 294 individuals from 26 groups, and samples were screened by polymerase chain reaction using pan-herpesvirus and HSV-1-specific assays. We found no evidence that human herpesviruses had infected free-ranging mountain gorillas. However, we found gorilla-specific homologs to human herpesviruses, including cytomegaloviruses (GbbCMV-1 and 2), a lymphocryptovirus (GbbLCV-1), and a new rhadinovirus (GbbRHV-1) with similar characteristics (i.e., timing of primary infection, shedding in multiple age groups, and potential modes of transmission) to their human counterparts, human cytomegalovirus, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, respectively.     

A Novel 2-dimensional Multiplex qPCR Assay for Single-Tube Detection of Nine Human Herpesviruses

Human herpesviruses are double-stranded DNA viruses that are classified into nine species. More than 90% of adults are ever infected with one or more herpesviruses. The symptoms of infection with different herpesviruses are diverse ranging from mild or asymptomatic infections to deadly diseases such as aggressive lymphomas and sarcomas. Timely and accurate detection of herpesvirus infection is critical for clinical management and treatment. In this study, we established a single-tube nonuple qPCR assay for detection of all nine herpesviruses using a 2-D multiplex qPCR method with a house-keeping gene as the internal control. The novel assay can detect and distinguish different herpesviruses with 30 to 300 copies per 25 μL single-tube reaction, and does not cross-react with 20 other human viruses, including DNA and RNA viruses. The robustness of the novel assay was evaluated using 170 clinical samples. The novel assay showed a high consistency (100%) with the single qPCR assay for HHVs detection. The features of simple, rapid, high sensitivity, specificity, and low cost make this assay a high potential to be widely used in clinical diagnosis and patient treatment.     

KSHV strategies for host dsDNA sensing machinery

The innate immune system utilizes pattern recognition receptors cyclic GMP-AMP synthase(cGAS)to sense cytosolic double-stranded(ds) DNA and initiate type 1 interferon signaling and autophagy pathway, which collaborate to limit pathogen infections as well as alarm the adaptive immune response. The genomes of herpesviruses are large dsDNA, which represent a major class of pathogen signatures recognized by cellular DNA sensor cGAS. However, to successfully establish the persistent infection, herpesviruses have evolved their viral genes to modulate different aspects of host immune signaling. This review summarizes the evasion strategies of host cGAS DNA sensing pathway by Kaposi's Sarcoma-associated Herpesvirus(KSHV) and their contributions to KSHV life cycles.     

Machinery to support genome segment inversion exists in a herpesvirus which does not naturally contain invertible elements

In many herpesviruses, genome segments flanked by inverted repeats invert during DNA replication. It is not known whether this inversion is a consequence of an inherently recombinagenic replicative mechanism common to all herpesviruses or whether the replication enzymes of viruses with invertible segments have specifically evolved additional enzymatic activities to drive inversion. By artificially inserting a fusion of terminal sequences into the genome of a virus which normally lacks invertible elements (murine cytomegalovirus), we created a genome composed of long and short segments flanked by 1,359- and 543-bp inverted repeats. Analysis of genomic DNA from this virus revealed that inversion of both segments generates equimolar amounts of four isomers during the viral propagation necessary to produce DNA for analysis from a single viral particle. We conclude that a herpesvirus which naturally lacks invertible elements is able to support efficient segment inversion. Thus, the potential to invert is probably inherent in the replication machinery of all herpesviruses, irrespective of genome structure, and therefore genomes with invertible elements could have evolved simply by acquisition of inverted repeats and without concomitant evolution of enzymatic activities to mediate inversion. Furthermore, the recombinagenicity of herpesvirus DNA replication must have some importance independent of genome segment inversion.     

Comparative Analysis of the Mosaic Genomes of Tailed Archaeal Viruses and Proviruses Suggests Common Themes for Virion Architecture and Assembly with Tailed Viruses of Bacteria

Tailed double-stranded DNA viruses (order Caudovirales) represent the dominant morphotype among viruses infecting bacteria. Analysis and comparison of complete genome sequences of tailed bacterial viruses provided insights into their origin and evolution. Structural and genomic studies have unexpectedly revealed that tailed bacterial viruses are evolutionarily related to eukaryotic herpesviruses. Organisms from the third domain of life, Archaea, are also infected by viruses that, in their overall morphology, resemble tailed viruses of bacteria. However, high-resolution structural information is currently unavailable for any of these viruses, and only a few complete genomes have been sequenced so far. Here we identified nine proviruses that are clearly related to tailed bacterial viruses and integrated into chromosomes of species belonging to four different taxonomic orders of the Archaea. This more than doubled the number of genome sequences available for comparative studies. Our analyses indicate that highly mosaic tailed archaeal virus genomes evolve by homologous and illegitimate recombination with genomes of other viruses, by diversification, and by acquisition of cellular genes. Comparative genomics of these viruses and related proviruses revealed a set of conserved genes encoding putative proteins similar to virion assembly and maturation, as well as genome packaging proteins of tailed bacterial viruses and herpesviruses. Furthermore, fold prediction and structural modeling experiments suggest that the major capsid proteins of tailed archaeal viruses adopt the same topology as the corresponding proteins of tailed bacterial viruses and eukaryotic herpesviruses. Data presented in this study strongly support the hypothesis that tailed viruses infecting archaea share a common ancestry with tailed bacterial viruses and herpesviruses.     

Inhibitory activity of (E)-5-(2-bromovinyl)-2'-deoxyuridine on the salmonid herpesviruses, Oncorhynchus masou virus (OMV) and Herpesvirus salmonis

The highly potent and selective anti-herpesvirus agent, (E)-5-(2-bromovinyl)-2'deoxyuridine (BVdU), was examined for its inhibitory effect on the salmonid herpesviruses Oncorhynchus masou virus (OMV) and Herpesvirus salmonis (H. salmonis). Minimum inhibitory concentrations (MIC) of BVdU for OMV and H. salmonis were 1.25 and 3.0 micrograms/ml, respectively; these values were equal to or higher than those obtained for acyclovir or cytarabine. OMV DNA polymerase activity was reduced in a dose-dependent fashion by BVdU 5'-triphosphate (BVdUTP) within the concentration range of 3 to 30 microM. However, BVdUTP could also be substituted for the natural substrate, TTP, in the OMV DNA polymerase assay. It is postulated that the inhibitory action of BVdU on the salmonid herpesviruses is more or less similar to that on other herpesviruses and resides with respect to the inhibition of the virus DNA polymerase activity as well as incorporation of BVdU into the viral DNA.     

T-cell transformation by Marek's disease virus

Marek's disease virus (MDV) is an avian herpesvirus that causes rapid development of T-cell lymphomas in chickens. The MDV genes currently thought to be involved in lymphomagenesis include a bZIP transactivator that is homologous to fos and jun oncogenes but do not appear to have counterparts in other oncogenic herpesviruses.     

嗜神经性疱疹病毒：神经科学研究的有力工具

病毒是研究现代神经科学的有力工具。对神经元的连接方式及功能研究大都是利用重组病毒完成的,嗜神经性疱疹病毒便是其中一种重要工具。随着基因工程学以及分子生物学技术的不断发展,多种嗜神经性疱疹病毒被改造为不同的重组病毒工具应用于神经科学研究。本文基于几种常见且应用较为广泛的嗜神经性疱疹病毒作为神经传导示踪工具、治疗神经性疾病的病毒载体和溶瘤病毒治疗神经肿瘤等应用进行阐述及讨论,为进一步开发嗜神经性疱疹病毒的功能提供参考。     

The genome of a very virulent Marek's disease virus

Here we present the first complete genomic sequence, with analysis, of a very virulent strain of Marek's disease virus serotype 1 (MDV1), Md5. The genome is 177,874 bp and is predicted to encode 103 proteins. MDV1 is colinear with the prototypic alphaherpesvirus herpes simplex virus type 1 (HSV-1) within the unique long (UL) region, and it is most similar at the amino acid level to MDV2, herpesvirus of turkeys (HVT), and nonavian herpesviruses equine herpesviruses 1 and 4. MDV1 encodes 55 HSV-1 UL homologues together with 6 additional UL proteins that are absent in nonavian herpesviruses. The unique short (US) region is colinear with and has greater than 99% nucleotide identity to that of MDV1 strain GA; however, an extra nucleotide sequence at the Md5 US/short terminal repeat boundary results in a shorter US region and the presence of a second gene (encoding MDV097) similar to the SORF2 gene. MD5, like HVT, encodes an ICP4 homologue that contains a 900-amino-acid amino-terminal extension not found in other herpesviruses. Putative virulence and host range gene products include the oncoprotein MEQ, oncogenicity-associated phosphoproteins pp38 and pp24, a lipase homologue, a CxC chemokine, and unique proteins of unknown function MDV087 and MDV097 (SORF2 homologues) and MDV093 (SORF4). Consistent with its virulent phenotype, Md5 contains only two copies of the 132-bp repeat which has previously been associated with viral attenuation and loss of oncogenicity.