Herpes Simplex Virus Ebooks Catalog

Stop Herpes Now

You'll discover: What foods are bad for you, encouraging outbreaks. What foods are good for discouraging outbreaks. The connection between genital herpes and stress. What herbs actually suppress the herpes virus. How to heal your body naturally and safely. How to manage stress in your life.

Stop Herpes Now Overview

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Lucke Tumor Herpesvirus

In size and structure, LTHV is similar to herpesviruses found in both higher vertebrates (humans) and lower vertebrates (fish). Virions in infected cell nuclei measure approximately 100 nm in diameter, with the size increasing after cellular membranes are acquired extracellular virus increases to about 170 nm (Fig. 1). AMPHIBIAN HERPESVIRUSES (HEHPCSWRfDAE) 51 The DNA of LTHV is a linear, double-stranded molecule with a base composition of 45 47 guanosine plus cytosine (G + C) and a molecular weight of 66 X 106, as determined by contour length measurement. If this value is confirmed by other methods of measurement, it is much lower than that of other herpesvirus DNAs. Figure 1 (A) Thin section of an inclusion-bearing Lucke tumor cell with typical herpesvirus particles in various stages of development in the nucleus. X19400. (B) Enveloped virions found extracellularly. x24 000. (C) Negatively stained nonenveloped particle showing typical herpesvirus morphology. x 110 000. (Reproduced...

HSV Infection during Pregnancy and Neonatal Disease

Localized genital infection is the most common form of HSV infection during pregnancy. In a small number of patients multiple visceral sites are also involved. Mortality among these pregnant women was reported to be > 50 , presumably due to altered cell-mediated immune responses. Fetal deaths occurred in 50 of cases, although mortality did not correlate with the death of the mother. Severe intrauterine fetal growth retardation was reported in women with primary HSV infection during pregnancy. Maternal primary infection before 20 weeks of gestation was associated with spontaneous abortion in as much as 25 of infected women. Fetal infection is generally due to virus shed at the time of delivery. Neonates have the highest frequency of visceral and CNS involvement of all HSV-infected patients. Skin lesions are the most commonly recognized features of the disease. However, at least 70 of untreated neonatal HSV cases will lead to

Epigenetic Modifications Regulate the Activity of a pHerpesvirus Promoter

P-Herpesviruses are highly species-specific viruses that grow slowly in cultured cells. The site(s) of residence for p-herpesviruses (monocytes and their bone marrow progenitors, endothelial cells) is still a subject of intensive research. Infection with human cytomegalovirus (HCMV, human herpesvirus 5, the best-characterized p-herpesvirus) and similar viruses isolated from other primates, domestic animals, and rodents causes typical cytopathologic changes involving cell enlargement. Honess et al. analyzed dinucleotide frequencies in herpesvirus DNA and observed a local deficiency of CpG dinucleotides in the major IE genes of hu man, murine, and simian cytomegalovirus genomes (Honess et al. 1989). The complete genome of human and murine cytomegalovirus is not CpG deficient as a matter of fact, the observed CpG frequency is higher than the expected one (Takacs et al. 2001b). Because a relative CpG deficiency and a surplus of TpG+CpA dinucleotides is thought to be a consequence of DNA...

Epigenetic Modifications of Latent yHerpesvirus Genomes

Y-Herpesviruses replicate in epithelial cells (lytic infection) and establish latency in lymphoid cells in vivo. In y-herpesvirus-infected lymphocytes and lymphoblastoid cell lines cultured in vitro, both virus production and tight latency can be observed. Latent y-herpesvirus transcripts frequently encode oncoproteins and protein non-coding small RNAs that may contribute to immortalization and malignant transformation of host cells. Although y-herpesviruses are favorite subjects of epigenetic studies, there are no data yetonthe associationoflatent, episomal y-herpesvirus genomes with different nuclear subcompartments (euchromatin or heterochromatin). Association of EBV genomes with the nuclear matrix (Jankelevich et al. 1992) and a colinear arrangement of the functional units of a 30-kb region the EBV genome with the rearranged human immunoglobulin gene loci (Niller et al. 2004a) suggest, however, that a viral LCR may control latent EBV gene expression in a host cell-dependent manner...

Herpes SimplexDRG Categr 283

There are two types of herpes simplex virus (HSV), type 1 and type 2. HSV-1 causes infection above the waist, such as cold sores that occur on the mouth. This type may occur in the genital area as a result of oral-genital sexual practices. After the initial infection, the virus is dormant, but the patient is a carrier and likely to have recurrent infections. Events that trigger recurrences are sun exposure, fever, menses, stress, or lack of sleep. Active HSV is associated with spontaneous abortion in the first trimester of pregnancy and an increased risk of preterm labor after 20 weeks' gestation. If a patient has active herpes around the time of the estimated date of delivery, cesarean section is the preferred method of delivery. Infected infants can develop the following signs and symptoms after an incubation period of 2 to 12 days fever, hypothermia, jaundice, seizures, poor feeding, and vesicular skin lesions.

Herpes ZosterDRG Category 272

I I erpes zoster, also known as shingles, is a common viral skin eruption that is estimated to affect 300,000 to 500,000 persons a year in the United States. Approximately 95 of adults in the United States have antibodies to the varicella zoster virus (VZV), which means they have been exposed to it. The virus causes acute unilateral inflammation of a dorsal root ganglion. Each nerve innervates a particular skin area on the body called a dermatome, which bends around the body in a pattern that has been mapped corresponding to the vertebral source. Generally, herpes zoster eruptions occur in the thoracic region and, less commonly, affect a single cervical, facial (trigeminal nerve), lumbar, or sacral ganglion. 422 Herpes Zoster (Shingles)

Methylation Patterns of Herpesvirus Saimiri DNA In Vitro and In Vivo

Herpesvirus saimiri causes lymphoma or leukemia in certain New World primates. The virion DNA was found to be unmethylated (Desrosiers 1982), but methylated viral DNA molecules were detected in lymphoid tumor cell lines (Desrosiers et al. 1979) and in DNA samples isolated from peripheral blood of one owl monkey and three white-lipped marmosets with leukemia (Desrosiers 1982). This suggests that de novo methylation of the viral genomes occurred in vivo and was not a result of prolonged in vitro cultivation of the tumor cells. Using CpG methylation-sensitive and resistant isoschizomers, an unmethylated region was also mapped in viral genomes carried by a cell line established from a marmoset tumor (Desrosiers 1982).

Classification of Cytomegaloviruses

Cytomegaloviruses (CMVs) are large, enveloped, double-stranded DNA viruses with an icosahedral capsid that belong to subfamily Betaherpesvirinae of the family Herpesviridae. There are three genera. Genus Cytomegalovirus contains human cytomegalovirus (HCMV species Human herpesvirus 5) and a number of other primate CMVs. Genus Muromega-lovirus contains murine cytomegalovirus (MCMV Murid herpesvirus 1) and rat cytomegalovirus (RCMV Murid herpesvirus 2). Genus Roseolovirus contains human herpesviruses 6 and 7 (HHV-6 and HHV-7 Human herpesvirus 6 and Human herpesvirus 7). Other CMVs that have not yet been fully classified within the Betaherpesvirinae are guinea pig cytomegalovirus (GPCMV Caviid herpesvirus 2), tree shrew herpesvirus (THV Tupaiid herpesvirus 1), swine cytomegalovirus (SuHV-2 suid herpesvirus 2), European ground squirrel cytomegalovirus (ScHV-1 sciurid herpes-virus 1), and American ground squirrel cytomegalovirus (ScHV-2 sciurid herpesvirus 2).

Murine Cytomegalovirus

Murid herpesvirus 1 is the type species of the genus Muromegalovirus. The term murine cytomegalovirus (MCMV) is more commonly used for the virus than murid herpesvirus 1. The natural host for MCMV is the house mouse, Mus musculus domesticus. Because of the strict species specificity of CMVs, MCMV is widely used as an animal model of HCMV infection. Consequently, more is known about MCMV than any other nonprimate CMV. The viral capsid is composed of 162 capsomers comprising hexons and pentons in a T 16 icosohedral lattice structure. The capsids of CMVs are larger and incorporate a larger genome than other herpesviruses. Unlike other CMVs, MCMV preparations may contain a high proportion of multicapsid virions, which contain a number of capsids enclosed within a common membrane. The capsid of MCMV is composed of five proteins the major capsid protein (MCP), the minor capsid protein, the minor capsid binding protein, the smallest capsid protein, and an assembly protease. These are encoded...

Reactivation of yHerpesviruses A Dual Role for DNA Methylation

Productive (lytic) replication of herpesviruses can be induced in cells carrying latent viral genomes by activation of IE genes. IE gene products activate thereafter transcription of lytic viral genes in a cascade-like manner. The promoter for the 0RF50 gene encoding Lyta (KSHV Rta), an IE protein of Kaposi's sarcoma-associated herpesvirus (KSHV human herpesvirus 8), was heavily methylated in primary effusion lymphoma (PEL)-derived cell lines during latency, but induction of the lytic cycle by 12- O-tetradecanoylphorbol-13-acetate (TPA) caused Lyta promoter demethylation (Chen et al. 2001). This suggests that KSHV maintains latency by controlling (repressing) the activity of a key promoter, Lyta, via DNA methylation. In contrast, demethylation impairs activation of Rp, the IE promoter for the BRLF1 gene of EBV, by the IE protein BZLF1 (Z) (Bhende et al. 2004). Bhende et al. suggest that preferential

Other Nonprimate Cytomegaloviruses

Swine cytomegalovirus is endemic in swine herds worldwide, and has also been shown to reactivate from pig-to-baboon xenotransplants. It causes rhinitis in young swine and is able to cross the placenta, resulting in generalized disease, runting, and fetal death. Initial sequence analysis of the DNA polymerase complex genes suggests that this virus is more closely related to HHV-6 than to CMVs. Tree shrew herpesvirus has been sequenced and has been found to resemble MCMV and other betaher-pesviruses. A CMV has been isolated from deer mice (Peromyscus maniculatas) in North America, and has been characterized as a CMV based on physical and biological properties and genetic homology with several genes of other CMVs. CMVs have also been isolated from European and American ground squirrels, and designated as sciurid herpesvirus 1 and sciurid herpesvirus 2, respectively. See also Cytomegaloviruses Simian Cytomegaloviruses.

Activator Repressor Complexes and Histone Modifications in Regulatory Regions of yHerpesvirus Genomes

A series of cell type-specific or general transcription factors bind to regulatory regions of y-herpesviruses. Most of them were identified in in vitro experiments. In vivo footprinting studies partly supported and partly extended these results. A consequent finding at the EBNA 2-activated Cp and LMP2Ap of EBV was the presence of a CBF1 footprint(s) in cells actively using these promoters and the absence of a typical CBF1 footprint in cells with silent Cp and LMP2Ap (Salamon et al. 2001,2003). This implies that although CBF1 is present in cells with silent Cp and LMP2Ap, in the absence of EBNA 2 it does not bind to its recognition sites.

The Herpesvirus Model

Additional features characteristic of latent infections can be identified through a more detailed consideration of latent infections engendered by the herpes simplex virus and Epstein-Barr virus (EBV). The herpesviruses, particularly herpes simplex virus, are the classic examples of latent agents, and latent infections are basic to their natural history. Hepadnavirus Hepatocytes, Herpesviruses (a) Herpes simplex 1 and 2 Neurons Episomal No macrophages (e) Human herpesviruses 6,7,8 Probably T lymphocytes Papillomaviruses Keratinizing epithelial cells Integrated and episomal No Parvoviruses Epithelial cells Integrated No Polyomaviruses Probably integrated Probably Retroviruses Herpes simplex virus The relevant pathogenesis of herpes simplex virus involves infection and viral replication at the body surface, followed by the passage of the virus (or, more probably, the viral nucleocapsid) to the regional sensory ganglion by fast axonal transport in the associated sensory nerve. At this...

Herpes Simplex Resistance History

Acyclovir (ACV) is the gold standard for the treatment of HSV infections. This drug is a nucleoside analogue of guanosine that has to be phosphorylated three times. The first phosphorylation is achieved by the thymidine kinase (TK) encoded by the virus this step is important as it allows ACV to become active only in infected cells. The second and third phosphorylations are carried out by cellular thymidylate kinases. Acyclovir triphosphate is a competitive inhibitor of viral DNA polymerase and is a DNA chain terminator. 1 Herpes simplex virus strains resistant to ACV have been reported since 1982. 2 They were most often recovered from immunocompromised patients previously treated with ACV. 3 Herpes simplex virus resistance to ACV may be associated with a mutation in one of the two viral enzymes involved in ACV mechanism of action TK and or DNA polymerase. Mutations occurring in the viral gene encoding TK are the most frequent and 95 of ACV-resistant isolates present a TK-deficient...

Quantitative Taq Man Assay for the Detection and Monitoring of Cytomegalovirus Infection in Organ Transplant Patients

Quantitative polymerase chain reaction assays have become the most common methods in the determination of viral load during cytomegalovirus (CMV) infection of transplant patients. In recent years, the development of automated nucleic acid extraction devices together with the introduction of real-time technology have been important elements for improvements of these assays. Key Words Automated nucleic acid extraction cytomegalovirus (CMV) MagNA Pure LC organ transplant patient plasma quantitation real-time PCR TaqMan viral load. Over the past recent years, the knowledge of the clinical significance, diagnosis, and management of cytomegalovirus (CMV) infection and disease in transplant patients has increased considerably. Major advances have been achieved through the development of new diagnostic techniques for the detection of the virus and through the use of antiviral agents. Most centers have protocols for the frequent monitoring of transplant recipients for CMV and 1. Human...

Herpesvirus Saimiri and Herpesvirus Ateles

This section focuses on the basic biology, gene content, and viral mechanisms of oncogenic transformation of HVS and HVA, and their possible applications as T-cell vectors and in cell-based immunotherapy. These gamma-herpesviruses must not be confused with two alphaher-pesviruses isolated from the same host species, designated as species Saimiriine herpesvirus 1 and Ateline herpesvirus 1, respectively. HVA can be isolated at a high frequency from spider monkeys (Ateles spp.). Strain 810 from A. geoffroyii is a member of species Ateline herpesvirus 2, whereas strain 73 and related strains (87, 93, and 94) from A. paniscus are isolates of ateline herpesvirus 3. HVA replicates in OMK cells, but remains mostly cell-associated with syncytia formation. As a result, supernatants of such cultures have low, unstable virus titers. In all gammaherpesviruses, the genes that are conserved among the herpesvirus subfamilies are arranged in blocks. Flanking or interspersed among the blocks are other...

Conditions That May Simulate Herpes Zoster

Herpes Simplex HSV in a linear distribution may be clinically impossible to distinguish from herpes zoster. Linear lesions are more common in children and with HSV on the extremities. Groups of lesions in different stages of evolution and pain or dysesthesia favor zoster. Culture, RIF, and PCR testing will distinguish the two.

Herpesvirus Vectors

Two herpesviruses are emerging as alternatives for the development of gene transfer vectors herpes simplex virus (HSV) and Epstein-Barr virus (EBV). HSV has a genome of approximately 155 kb in length, which is maintained as a concatemerized circular or linear episome in infected cells. It efficiently infects cells, including nondividing cells, from a wide variety of organisms, and is able to establish a persistent infection. Its genome can accommodate large amounts of foreign DNA, and a number of vector systems have been developed. The EBV-based systems have not been developed as extensively and currently employ replication-defective EBV strains. Unlike HSV, EBV vectors have a very limited tropism and their possible usefulness remains to be explored. The main difficulty using these two systems is the need for almost complete virus genomes that are very complex and large in size, making manipulations exceedingly difficult. The eventual usefulness of these systems will be dictated by...

How Many Herpesviruses Have Been Discovered

Since the publication ofthese methods, the number ofnovel herpesviruses discovered has risen very fast. Prior to writing this article, more than 200 potential herpesvirus species had been detected, belonging to more than 20 mammalian orders (Table 1). These are many more than currently accepted by the International Committee on Taxonomy of Viruses (ICTV), which lists some 120 herpesvirus species (Vlllth Report). Sequences of more than 160 herpesviruses are available under the taxonomy browser of the NCBI, most detected by DPOL consensus primers. In addition, sequences indicating the existence of more than 100 additional herpesvirus species, not yet available in public databases, await publication. By combining all the data currently available, a total of approximately 300 detected

Panherpes PCR with Degenerate Primers

The method is based on the fact that herpesvirus genomes contain highly conserved genes, which are present in all because they code for proteins essential for viral growth. One of the most conserved is the herpesvirus DNA polymerase (DPOL) gene. Investigators aligned the DPOL genes of all herpesviruses for which sequence data were available, in order to identify short blocks of greatest amino acid identity that encode domains essential for DPOL function. This procedure allowed the design of five degenerate primers that were used in a nested PCR -three primers in the first round and two primers in the second round (Figure 1). The region amplified in between the primers displayed a lower degree of conservation. This allowed investigators to assess (1) whether the detected herpesvirus was known or novel, and (2) to which herpesvirus subfamily the novel species could be assigned. In some cases, even a tentative assignment to a virus genus was possible. The primers are degenerate in their...

History of Herpesvirus Discovery

Diseases caused by herpesviruses have been known since ancient times, but it was not until the beginning of the twentieth century that the viruses causing these diseases were detected. Human alphaherpesviruses (members of subfamily Alphaherpesvirinae) such as herpes simplex virus (HSV) and varicella-zoster virus (VZV) were the first to be propagated in cell culture and visualized by electron microscopy. Later, betaherpesviruses (members of subfamily Betaherpesvirinae) such as human cytomegalovirus (HCMV) and gammaherpesviruses (members of subfamily Gammaherpesvirinae) such as Epstein-Barr virus (EBV) were discovered and studied in detail. EBV was the first herpesvirus whose genome was cloned in bacteria and completely sequenced. In the middle of the last decade of the twentieth century, the complete genome sequences of roughly 40 herpesvirus species had accumulated in public databases. These human and animal her-pesviruses had previously all been cultured, and their physical,...

Epigenetic Modifications of aHerpesvirus Genomes

A-Herpesviruses have a relatively short reproductive cycle and their productive (lytic) replication results in destruction of the infected cells. In vitro they spread rapidly after infection in sensitive cell types. In vivo they establish latency first in sensory ganglia and in cells of the central nervous system, although equine herpesvirus 1 and equine herpesvirus 4 target the lymphoretic-ular system (Welch et al. 1992) and latent Marek's disease virus genomes are associated with lymphomas in chicken (reviewed by Morimura et al. 1998). T lymphoblastoid cell lines derived from such lymphomas carry methylated viral genomes (Kanamori et al. 1987). The latent genomes of herpes simplex virus are associated with nucleosomes (Deshamne and Fraser 1989) and exist in an extrachromosomal (episomal) state (Mellerick and Fraser 1987). Depending on the host cell, both DNA methylation and modification of histone tails may affect expression of the best-characterized a-herpesvirus genomes.

Herpes and Varicella Zoster

Impetigo Eyelid

INTRODUCTION Herpes zoster (shingles) and varicella zoster (chickenpox) are both systemic infections with manifestations caused by herpes virus varicellae. The virus is an obligate human parasite requiring person-to-person transmission for its survival. Varicella most commonly occurs in children and is almost always a mild, self-limited disease however, when the disease occurs in adults it is often a much more severe process. Zoster, meaning belt or girdle in Greek, is felt to be a reactivation of a previous varicella infection within a single dermatome. Herpes zoster is most prevalent in middle to late adulthood however, it can occur in children and rarely even in infants, in whom it is usually a mild disease. Eyelid symptoms result from involvement of the first or ophthalmic division of the trigeminal (5th cranial) nerve and are seen in up to 10 of cases of zoster infections. Adults with herpes zoster are contagious during the early stages and often transmit the virus to susceptible...

Epigenotypes of Latent Herpesvirus Genomes

2 Epigenetic Modifications of a-Herpesvirus Genomes 64 of a p-Herpesvirus 4 Epigenetic Modifications of Latent y-Herpesvirus Genomes 67 4.1 Methylation Patterns of Herpesvirus Saimiri DNA In Vitro and In Vivo . . 68 4.3 Reactivation of y-Herpesviruses A Dual Role for DNA Methylation 72 in Regulatory Regions of y-Herpesvirus Abstract Epigenotypes are modified cellular or viral genotypes which differ in tran-scriptional activity in spite of having an identical (or nearly identical) DNA sequence. Restricted expression of latent, episomal herpesvirus genomes is also due to epigenetic modifications. There is no virus production (lytic viral replication, associated with the expression of all viral genes) in tight latency. In vitro experiments demonstrated that DNA methylation could influence the activity of latent (and or crucial lytic) promoters of prototype strains belonging to the three herpesvirus subfamilies (a-, p-, and y-herpesviruses). In vivo, however, DNA methylation is not a...

Conditions That May Simulate Herpes Simplex Recidivans

Both diseases are common in the central facial region, and both begin with small clear vesicles on an inflammatory base. Herpetic lesions tend to remain fixed and discrete, and the vesicles are small, 1 to 2 mm across, tightly grouped, and persist for longer periods. Facial HSV occasionally develops secondary impetigo, causing some diagnostic confusion. A smear with a Gram stain will often show bacteria with cases of impetigo. A Tzanck smear of a blister base will show herpes virus cytopathic effect with herpes labialis. RIF test is also positive with herpes. Bacterial and viral cultures are expensive and are seldom justified. Differentiation of herpetic and bacterial lesions in periungual locations requires a high index of suspicion. The thick epidermis in these acral areas disguises the morphology of the herpetic lesion, which usually presents as an acute inflammatory pustule. Viral lymphangitis is common. Clear unilocular or multilocular vesicles should suggest herpes. Recurrent...

Herpesviruses

Herpes simplex virus (HSV) and varicella virus (VZV) In spite of the awareness of the risks of sexually transmitted diseases during this era of the acquired immune deficiency syndrome (AIDS), the incidence of genital herpetic infection has continued to increase dramatically, so that today it is estimated that about 20 of the sexually active population of the USA may suffer from herpes genitalis. As with all herpesvirus infections, primary genital infection results in latency and periodic recurrences in the anal genital area. The second major HSV-associated disease is generally the cosmetic nuisance resulting from HSV oral infection and resulting in herpes labialis (cold sores) in about 90 million people in the USA. Although experimental vaccines are being developed, none is approved, indicating the continuing need for effective antiviral therapy. For VZV the situation is quite different. This ubiquitous virus is responsible for the systemic disease of chickenpox, usually in children,...

IHerpesviridae

Isolated similar viruses from patients with acquired immune deficiency syndrome (AIDS) and children with exanthem subitum, and revealed that the virus is predominantly T lymphotropic. The name of the virus was changed to human herpesvirus 6 because it was a newly discovered one distinguished from other five known human herpesviruses. HHV-6 isolates are classified into two groups as variants A (HHV-6A) and B (HHV-6B). The two variants are closely related but show consistent differences in biological, immunological, epidemiological and molecular properties. HHV-6B is the major causative agent of exanthem subitum, but no disease has yet been associated with HHV-6A. HHV-7 was isolated by Frenkel et al in 1990, as the seventh human herpesvirus, from CD44- lymphocytes of a healthy adult. The virus also causes exanthem subitum.

Herpes Simplex

Eosiniphlic Keratynocytes

INTRODUCTION Herpes simplex is caused by a DNA virus that is estimated to infect 60 to 90 of individuals at sometime during their life. Clinically evident infections however are much less common. Involvement of the facial region is predominantly due to type I herpes virus, with the exception of newborns, in whom overwhelming exposure to the type II variety during birth can result in development of typical skin lesions during the first few days of life, often associated with devastating CNS and systemic involvement. Primary herpes occurs in previously uninfected individuals. The chief mode of transmission is by kissing or other forms of intimate contact with an individual who has an active, usually recurrent, herpetic lesion. CLINICAL PRESENTATION Following a 2 to 14 day incubation period there develops a mild fever with moderately painful, usually unilateral, edema and erythema of the eyelid region. This is soon followed by the development of multiple discrete 2 to 3 mm vesicles that...

Herpesviridae

Herpesviruses have been isolated from channel catfish (Ictalurus punctatus), common and koi carp (C. carpio), common goldfish ( Carassius auratus), eel (Anguilla spp.), rainbow trout, masou salmon, lake trout (S. namaycush), sturgeon, walleye, and Japanese flounder. Channel catfish virus is the only fish herpesvirus assigned to the genus, Ictalurivirus, and this genus is not assigned to any of the three subfamilies (Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesviri-nae) of the family Herpesviridae. The other fish herpesviruses, cyprinid herpesviruses 1 and 2 (CyHV-1 and CyHV-2), koi herpesvirus (CyHV-3), salmonid herpesvirus 1 and 2 (SalHV-1 and -2), eel herpesvirus (Anguilla herpesvirus, AngHV-1), and the acipenserid or white sturgeon herpesviruses remain as unassigned members of the family Herpesviridae. Electron micrographic evidence of herpes-viruses has been found in sharks, eels, pike, flounder, perch, angelfish, grouper, and other fish. The genomes of fish...

Viruses Associated with Inhibition or Suppression of Apoptosis

Herpesviridae This family of viruses contains members that bring about many different responses and diseases in the host. These viruses encode many different genes that affect PCD of the infected cell. Normally, herpes simplex virus type 1 (HSV-1) does not induce apoptosis, however, if ICP4 is deleted, apoptosis ensues. Thus, ICP4 blocks apoptosis, perhaps allowing cells to become latent. The HSV US3 gene, which encodes a serine threonine protein kinase, also protects against apoptosis. The late y34.5 gene inhibits apoptosis in infected neurons and promotes neurovirulence and could underlie HSV-mediated encephalitis. HSV-2-inhibits FAS ligand expression on the surface. PCD of cells infected with these herpesviruses results in decreased virus production. In herpes saimiri, ORF 16, is also a bcl-2 homologue. Several gamma-herpesviruses, including Kaposi's sarcoma herpesvirus (KSHV, HHV-8), E8 protein is a v-FLIP, which is a death effector domain (DED)-containing protein that interferes...

Adenoassociated Virus

Adeno-associated virus is a small, DNA-containing parvovirus that has been isolated from humans and other animal species. 1-4 Several serotypes of AAV have been isolated from humans and nonhuman primates. 1,4 Adeno-associated virus is defective and replicates only in host cell nuclei when certain functions are provided by a coinfecting helper adenovirus (Ad) or herpesvirus.1-1,2-1 The mechanism of the helper function is not clearly defined but only a limited set of adenovirus genes, E1, E2A, E4, and the VA RNA are required. 1 Adeno-associated virus has a broad host range but the efficiency of transduction with AAV vectors of different serotypes varies because of differences in cell receptors utilized for entry, cellular trafficking of AAV particles, and uncoating of the viral genome in the cell nucleus. For AAV to replicate, or to function as a gene delivery vehicle, the uncoated single-stranded DNA genome must be converted to a double-stranded molecule to permit transcription and...

Design and Production of AAV Vectors

In DNA transfection-based systems, human 293 cells are transfected with DNA plasmids containing the AAV vector cassette, the rep and cap genes, and the adenovirus E2A, E4, and VA genes. Alternatively, stable producer cell lines that contain the rep and cap complementing genes and the vector genome are infected with Ad. Producer cell lines are readily scalable AAV, but a new producer cell line must be generated for each individual AAV vector. A third approach uses a packaging cell line containing a rep-cap gene cassette that is then coinfected with an Ad AAV hybrid virus, which is an E1 gene-deleted Ad containing the AAV-ITR vector cassette, and Ad to provide E1. After infection, the rep-cap genes, the AAV-ITR cassette is amplified and packaged into AAV particles. The same packaging cell line can be used for production of different AAV vectors simply by changing the Ad AAV hybrid virus. Variations of these methods use herpes simplex virus (HSV) in the production of AAV vectors by...

Virion and Genome Structure and Composition

As indicated by the size and complexity of the virions, the genome of ascoviruses is large, and consists of a single molecule of dsDNA, which, depending on the viral species, is either in the range of 116 kb in size (Diadromus ascovirus), 140 kb (Spodoptera ascovirus) or 180 kb (Trichoplusia ascovirus). The G + C content of the Spodoptera ascovirus is 60 , whereas for the Trichoplusia ascovirus it is 42 . Supercoiled circular DNA has not been detected in cesium chloride gradients, nor have circular forms been observed by electron microscopy. The DNA genome is therefore referred to as linear, though each terminus may consist of a short single-stranded loop connecting the stands, making the molecule circular, as occurs in herpes-

Results in the VTA and Substantia Nigra

Another finding relevant to this controversy is that overexpression of GluRl in the rostral VTA using a herpes simplex virus resulted in intensification of the locomotor stimulant and rewarding properties of morphine (16,17). Although this is an interesting finding, it does not necessarily imply that increased GluRl expression is involved in the naturally occurring pathways that produce behavioral sensitization to morphine or psychomotor stimulants. A state resembling behavioral sensitization can be produced by a number of diverse experimental manipulations, all sharing the ability to produce brief but intense activation of VTA DA cells. These include repeated electrical stimulation of the VTA (18) or PFC (19), and pharmacological disinhibition of VTA DA cells (20).

Replication and Morphogenesis

Though there have been no biochemical studies of viral DNA replication or protein synthesis, studies carried out with the Trichoplusia and Spodoptera ascoviruses in vitro in insect cell lines show that progeny virions first appear about 12 h after infection. Virion morphogenesis is initiated after the nucleus ruptures, and occurs before and during the cleavage of the cell into vesicles. The first recognizable structural component of the virion to form is the multilaminar layer of the inner particle. Based on its ultrastructure, this layer consists of a unit membrane and an exterior layer of protein subunits. As the multilaminar layer assembles, a dense nucleoprotein core aggregates on the interior surface. This process continues until the inner particle is complete. After formation, the inner particle is enveloped by membranes within the cell or vesicle. These membranes are apparently synthesized de novo. Thus, the assembly of the virions is reminiscent of that in other viruses with...

Future Perspectives

Some of the initial studies on molecular mimicry and virus-induced autoimmunity indicated that viruses share common sequences with host components. It has been demonstrated that some viruses have acquired host genes and modified these to subvert the immune system. Herpesviruses encode MHC-like molecules, Fc receptors, IL-10-like factor and complement regulatory proteins, and poxviruses have incorporated into their genome, IL-1 receptor, tumor necrosis factor (TNF) receptor, IFN-y receptors and complement control proteins. In addition, viral proteins need to perform specific functions in the cell to replicate its genome and assemble new virions. These functions use the existing cellular machinery and therefore mimic many of the host cells, which also perform similar tasks. The key question is still how are these infections which are associated with autoimmune disease able to initiate the pathway leading to self-reactive immune responses

Results in the NAc and Striatum

Chronic cocaine treatment leads to accumulation in some NAc neurons of stable isoforms of the transcription factor AFosB, so Kelz et al. (45) used transgenic mice in which AFosB was induced in a subset of NAc neurons to model chronic cocaine treatment. These mice showed increased responsiveness to rewarding and locomotor-activating effects of cocaine, as well as increased expression of GluR2 in the NAc but not dorsal striatum. In a place conditioning test, rats that received intra-NAc injections of a recombinant herpes simplex virus vector encoding GluR2 spent more time in a cocaine-paired chamber than controls, while rats made to overexpress GluRl spent less time in the cocaine-paired environment. Although this suggests that increased NAc levels of GluR2 may account for enhanced rewarding effects of cocaine in the AFosB-expressing mice, more work is needed to evaluate the relevance of these findings to the intact cocaine-treated animal.

Opportunistic Infections and Malignancies Associated with HIV Infection

HIV-associated OI or malignancy, or less commonly 'uncovering' of previously unrecognized and untreated diseases. Shingles (re-emergence of the chicken pox virus, Varicella zoster virus), other Herpes viruses, and mycobacterial infections are especially common in IRIS. With better global access to HAART, including Africa and Asia, an increasing number of cases of IRIS are being reported especially in areas with high prevalence of diseases like tuberculosis.

HIV and Kidney Disease

Necrosis may occur secondary to hypotension, sepsis, or nephrotoxic drugs. Some agents used for treatment of Ols in HIV-infected patients, such as amphotericin B, aminoglycosides, foscarnet, and trimethoprim-sulpha-methoxazole require careful renal monitoring. Post-renal etiologies in the setting of HIV may include outflow obstruction secondary to tumor, lymphadenopathy or fungus balls, and medication related nephrolithiasis as seen with the antiretroviral medications indinavir and atazanavir, and with sulfadiazine and acyclovir. Acute renal failure secondary to interstitial nephritis as a manifestation of IRIS has also been reported.

Geographic Distribution

Increasing numbers of gammaherpesviruses have been identified in normally free-ranging (exotic) ruminant species that have been farmed or held in zoological collections, and several of these viruses have caused MCF-like syndromes when transmitted to other in-contact ruminant species. At least six members of the MCF virus group of ruminant gammaherpesviruses have been identified thus far. Four of these viruses are clearly associated with clinical disease alcelaphine herpesvirus 1 (AlHV-1) carried by wildebeest (Connochaetes spp.) ovine herpesvirus 2 (OvHV-2), ubiquitous in domestic sheep caprine herpesvirus 2 (CapHV-2), endemic in domestic goats and the virus of unknown origin that caused classic MCF in white-tailed deer (Odocoileus virginianus MCFV-WTD). Gammaherpesviruses in the MCF virus group have been found in musk ox (Ovibos moschatus), Nubian ibex (Capra nubiana), and gemsbok (South African oryx, Oryx gazella). Gammaherpesviruses have also been found in bighorn sheep, bison,...

Prevention and Control

Vaccines are not generally available for the control of other bovine or other ruminant herpesvirus diseases. Since MCF is acquired from a heterologous host (wildebeest, sheep, goats, or other ruminant species), it is clearly preventable by avoiding such contacts. The often-sporadic nature of the disease and the lack of detailed knowledge of the putative sheep-associated virus make avoidance difficult. In zoological collections, bovid species known to harbor alcelaphine herpesviruses 1 and 2 or any of the other gammaherpesviruses should not be cohabited with those species known to be susceptible to MCF.

Evolutionary Conservation Of Bcl2 Family Proteins

Notably, this family of proteins is evolutionarily conserved. A number of viruses encode Bcl-2 homologs, including most, if not all, gamma herpes viruses (7). Most of these viral homologs are anti-apoptotic, probably because viruses need to keep the infected cells alive for latent and persistent infection (7,8). The nematode Caenorhabditis elegans has its own sequence and functional homologs for a death antagonist, CED-9 (9), and a BH3-only death agonist, EGL-1 (10). On the other hand, only prodeath homologs (dBorg-1 Drob-1 Debcl and dBorg-2 Buffy) have been described in the Drosophila (11). These homologs are discussed in details in Chapters 9 and 10, respectively.

Clinical manifestation

Differential diagnosis Bullous pemphigoid linear IgA dermatosis erythema multiforme Stevens-Johnson syndrome epidermolysis bullosa epider-molysis bullosa acquisita dermatitis herpe-tiformis impetigo pemphigus foliaceus pemphigus vulgaris herpes simplex virus infection herpes zoster

Viral Subversion of Antigen Presentation

Migration of DCs is a crucial step in initiating the adaptive immune response. Examples of viruses that have developed mechanisms to prevent migration of infected DCs to lymphoid organs are herpes simplex virus (HSV) 1 and human cytomegalovirus (HCMV). In both cases, there is an inhibition of complete DC maturation and subsequent expression of chemokine homing receptors. In addition, HCMV inhibits DC migration one step further by preventing APCs from arriving at a site of infection by producing homologs of chemokines that interfere with host pro-inflammatory chemokine gradients. Another effective immune-evasion strategy used by viruses to disrupt APCs is the prevention of or interference with antigen-specific T-cell activation. The ability to disrupt MHC peptide binding has evolved in many different virus species including adenovirus and human immunodeficiency virus (HIV). Herpesviruses have also evolved to block host cell antigen presentation. Some mechanisms utilized by...

History and Classification

Level but distinct crossneutralization of CHP and Piry viruses with VSV-IND was previously reported. However, subsequent studies using hyperimmune guinea pig as well as rabbit serum failed to detect any crossreactivity between these viruses, even when the infective ribonucleoprotein (RNP) particles were used, indicating that these viruses possess distinct antigenic determinants. The Piry virus constituent proteins were also found to be antigenically distinct from several other viruses such as lymphocytic choriomeningitis virus, herpes simplex virus, and 62 arboviruses.

The First Uncertain Steps

Within a few days of treatment and the resistant virus spread readily to contacts. The first nucleoside analogs, with antiviral activity, emerged during the search for drugs to treat cancer. The first of these, idoxuridine (IDU), was discovered to be active against herpes viruses by Dr. William (Bill) Prusoff in 1959. However, its toxicity limited its use to topical treatments only (e.g., infections of the eye). Vidar-abine (Ara A) was slightly more selective its main systemic use was to treat herpes encephalitis. No convincing selective antiviral compound had yet been discovered.

The Major Breakthrough

The discovery of the antiherpes drug, acyclovir (ACV) in 1978, was the major milestone in antiviral therapy. For the first time, it was demonstrated that an effective, non-toxic, antiviral drug is an achievable aim. Moreover, chronic suppressive acyclovir therapy for several years, to prevent the misery of recurrent herpes, is possible without adverse effects. More than two decades of worldwide use has proved that acyclovir is one of the safest drugs in clinical therapy. Acyclovir proved that not all nucleoside analogs had to be mutagenic and or carcinogenic. The early doubts, about the potential for discovering safe antiviral agents, were dispelled for ever. The selectivity of acyclovir for the herpes viruses is dependent on it being activated only in herpes virus-infected cells. The critical initial step in that activation is its phosphorylation to ACV-monophosphate by the viral thymidine kinase. Cellular enzymes convert the monophosphate to the triphosphate which inhibits...

Important Classes of Antiviral Targets and Compounds

Nucleoside nucleotide analogs are the treatment of choice for herpes viruses and HBV. They are included as two or three components of HAART for HIV. For influenza, T-705 is a good candidate progressing through development. For HCV, viral polymerase inhibitors, such as R1626, are being developed.

Antiviral Combination Therapy

When the symptoms of an infection require treatment, then combining an antiviral agent with an immunomodulator, anesthetic, or anti-inflammatory substance may give added benefit. Thus, acyclovir has been combined with cortisone to simultaneously reduce pain and irritation of the herpes lesion at the same time reducing the replication ofinfectious virus which would otherwise be prolonged by the anti-inflammatory component. This concept is likely to be widened to other cases in which the inflammatory response plays an important role in the disease, for example, influenza. Virus latency remains an obstacle to successful antiviral chemotherapy for which no solution appears to be in sight. Members of the Herpesviridae are notable for being able to establish latent infections with HSV and VZV, latency is established in neuronal cells. During latent HSV-1 infection, the latency-associated transcript (LAT) of HSV-1 is the only known viral gene expressed. A micro-RNA (miR-LAT), which is...

Donor Insemination and Egg Donation

Donor insemination is used when sperm are incapable of fertilizing the egg. Usually this occurs if the male produces very little or no sperm. Sometimes, donor sperm is used when the male partner is the carrier of a genetic disorder that could be transmitted to the baby. Sperm donors should be between ages eighteen and fifty-five, and all should be screened for genetic disorders, such as cystic fibrosis, and for various types of chromosomal abnormalities and infectious disease, including hepatitis, syphilis, cytomegalovirus, and HIV. As with the use of intrauterine insemination, the female partner undergoes ovarian stimulation to maximize the number of follicles released during ovulation. Pregnancy rates resulting from the use of donor insemination are between 32 percent and 50 percent after ten inseminations.

Viral Regulators of the Mitochondrial Pathway

Viral homologs of the cellular anti-apoptotic protein Bcl-2 are encoded by the g-herpesviruses, including Epstein Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV HHV8), and several different poxviruses including the myxoma virus M11L protein and fowlpox virus-Bcl-2. Viral Bcl-2 proteins have the same three-dimensional structure as their cellular counterparts, but differ from the cellular factors in that vBcl-2 proteins are resistant to normal cellular regulatory mechanisms, such as cleavage by caspases, which can convert cellular Bcl-2 into a pro-death factor. Like cellular Bcl-2, vBcl-2 prevents permeabilization of the outer mitochondrial membrane by Bax and Bak, thereby preventing cyto-chrome c release and caspase activation (Figure 1). Adenovirus E1B-19K, vaccinia virus F1L, cytomegalovirus vMIA (viral mitochondrial inhibitor of apoptosis) and vICA (viral inhibitor of caspase-8 activation) proteins also function at the same step as Bcl-2 as they bind and regulate...

Gene Targeting And Knockout Genetics

The next question (of course) was to find in which cells this rare event was happening. In order to answer this question markers which could be detected in cell culture were inserted into the targeting vector. These markers can take several forms. In Figure 5.24 the markers are the 'neomycin resistance' (neor) gene without its promoter so that its expression depended on the targeted gene's promoter and (at the end of the base sequence) the thymidine kinase (tk) gene from the herpes virus. Whilst the neor is inserted into the centre of one of the targeting vector's exons, tk is attached at the end (Figure 5.24). It is known that terminal sequences are usually lost in homologous recombination. When the targeting vector finds its homologue on the culture cell's chromosome the integration events slot the homologous DNA into the host chromosome and eliminate or at least inactivate the tk. In the random case the entire sequence, including tk, is inserted into the host chromosome.

Replication and Virion Assembly

Although there have been few biochemical studies ofviral DNA replication or protein synthesis, studies carried out with ascoviruses in vivo and in vitro show that progeny virions first appear about 12 h after infection. Virion assembly is initiated after the nucleus ruptures, and occurs prior to and during the cleavage of the cell into viral vesicles. The first recognizable structural component of the virion to form is the multilaminar layer of the inner particle. Based on its ultrastructure, this layer consists of a unit membrane and an exterior layer of protein subunits. As the multilaminar layer assembles, a dense nucleoprotein core aggregates on the interior surface. This process continues until the inner particle is complete. After formation, the inner particle is enveloped by membranes within the cell or vesicle. These membranes are apparently synthesized de novo. Thus, the assembly of the virions is reminiscent of that in other viruses with complex virions, such as the...

Classification and Evolution

All of the animal CMVs described to date are members of the family Herpesviridae and belong to the Betaherpesvirinae subfamily of herpesviruses. Based on the relatively high (G+C) content of their DNA molecules and their adaptability to grow in fibroblasts in cell culture, most if not all of the traditionally recognized animal CMVs are likely to be evolutionarily more similar to the beta-1 subgroup that includes HCMV and MCMV than to the (A+T)-rich beta-2 subgroup exemplified by HHV-6. The International Committe on Taxonomy of Viruses has now classified betaherpesviruses into three distinct genera, Cytomegalovirus (HCMV-like), Muromega-lovirus (MCMV-like) and Roseolovirus (HHV-6, HHV-7), but it is likely that distinctions between the first two taxons at least will become murky when molecular genetic criteria (i.e. gene content and DNA and protein sequence similarities) are applied to those CMV species that infect other mammalian and primate hosts. The genomes of prototype species of...

Replication Strategies

All herpesviruses have enveloped icosahedral capsids and replicate in the nucleus, with expression of several immediate early regulatory proteins preceding expression of the early proteins, including the biochemical functions, viral DNA and late structural proteins. In cell culture, fully permissive host cell types for HCMV are restricted almost exclusively to diploid human fibroblasts (plus some astrocytomas and perhaps smooth muscle cells and differentiated macrophages), although even in fibroblasts fresh clinical isolates usually need to be adapted for efficient growth by multiple rounds of successive passaging (which is accompanied by gene losses at the L-segment unique-repeat boundaries). Laboratory strains of HCMV replicate their DNA efficiently by 72 h in human fibroblasts, but express only the MIE Figure 1 Infection of human diploid fibroblasts (HF cells) with both human and nonhuman primate cytomegaloviruses. HF cells at passage level 15 were infected and examined daily for...

Control of Gene Expression

The lytic cycle pathway of gene expression for animal CMVs follows the typical herpesvirus cascade of immediate early mRNA and proteins followed by activation of delayed early then late class genes. Similarly organized MIE transcription units, which encode regulatory proteins that trigger the lytic cycle, have been characterized in HCMV, ChCMV, AgCMV, RhCMV, BaCMV, GpCMV, RCMV, MCMV, and HHV-6 and HHV-7. In each case, these transcription units are oriented leftwards at genome map position 0.7 and produce several multiply-spliced mRNAs whose expression is controlled by powerful upstream cis-acting enhancer control regions. By far the most predominant viral mRNAs synthesized after infection of permissive cells in the presence of cycloheximide are these MIE mRNAs, which are also the only HCMV or AgCMV mRNAs and proteins produced after infection of nonpermissive rodent fibroblasts. At least two types of phosphorylated nuclear regulatory proteins are encoded by the MIE transcription unit....

Properties and Organization of Genome

DNA isolated from purified virions contains a single 3' nucleotide extension that may facilitate circularization to a prereplicative intermediate. Herpesvirus genomes are grouped (A F) according to sequence reiterations greater than 100 base pairs. Based on this scheme, the MCMV genome, consisting primarily of unique sequences, is catalogued with the group F genomes. However, clusters of 31-bp direct repeats delimit each terminus of the genome, and additional, nonhomologous, intra- and intergenic direct repeats punctuate the centralized unique region. Inverted repeats, present in the origin of replication and upstream of several ORFs, do not mediate isomerization.

Taxonomy and Classification

The formal designation given by the International Committee on Taxonomy of Viruses to human CMV is human herpesvirus 5 (HHV-5), a name that is not in common usage. Human CMV is the prototype of the genus Cytomegalovirus. Cytomegaloviruses share many characteristics with other herpesviruses, including typical virion morphology and large, linear DNA genome, as well as common biological properties such as persistence and latency in the host. These viruses have distinguishing characteristics as well, such as their well-established tropism for salivary glands, restriction to the host species of origin and slow growth in culture. These differentiating characteristics define the Betaherpesvirinae subfamily. In addition to the cytomegaloviruses, genome sequence analysis established that the betaherpesviruses include two lymphotropic human herpesviruses, HHV-6 (genus Roseolovirus) and HHV-7. Large-scale nucleotide sequence analysis of human CMV, murine CMV, HHV-6 and HHV-7 demonstrated a...

Geographic and Seasonal Distribution

Geographic, but not seasonal, variation in CMV transmission is known to occur. As is the case with other herpesviruses spread by direct contact and without much morbidity, the virus is distributed worldwide and appears in even the most remote populations. In urban environments, some regions of developed countries and all less developed countries, a high proportion (80-100 ) of the population is infected early in life, whereas in rural and suburban

Properties of the Virion

Typical of the herpesvirus group, the virion of huma cytomegalovirus (HCMV, human herpesvirus 5). is approximately 230 nm in diameter and is composed of a DNA-containing nucleocapsid, surrounded by a less structured tegument layer, and bounded by a trilami-nate membrane envelope. The nucleocapsid is icosa-hedral has an outside diameter of approximately sensitive to a compound, ganciclovir DHPG), that is structurally related to acyclovir but acts via a poorly understood process whereby another viral kinase (UL97) is responsible for its phosphorylation. Ganciclovir is administered parenterally or, at very high doses, orally and can control CMV infections. Because of the chronic immunocompromised settings where CMV emerges as a pathogen, prolonged treatment is often necessary and this leads to the emergence of drug-resistant mutants due to mutations in the UL97 kinase or the DNA polymerase. Another parenterally administered nucleotide analogue, cido-fovir has also been licensed for use...

Properties of the Proteins

HCMV proteins share the general pattern of expression characteristic of the herpesvirus group. Immediate early (a), early ( ) and late (y) proteins are synthesized sequentially from corresponding mRNAs whose transcription is regulated in a temporal cascade (see Characterization of Transcription below). Immediate early proteins are required to regulate transcription from their own promoters and those of subsequently expressed genes. Early proteins include many of the enzymes and regulatory factors needed to carry out the synthesis of progeny DNA and proteins. Late proteins include most of the virion structural proteins. Members of all three classes have been described for HCMV, but only a small number of its more than 200 potential proteins have been identified. Those that have been reported include both nonvirion and virion species and their properties are briefly described below.

Response to Infection Host immune response

Autoimmunity is a common manifestation of cytomegalovirus infections. Thymic involution may impair the elimination of autoreactive T cells, thus promoting autoimmunity. CD4+-dependent antibody profiles are altered showing increases in serum immunoglobulin (reactive with autologous tissues and ovalbumin) levels in general and 6-20-fold increases in IgG3 and IgG2b levels specifically. Antibodies with specificity toward the 98-kDa structural protein are neutralizing, but are also cross-reactive with mouse neurofilament protein (NFP), which is a component of the central and peripheral nervous systems, and to a lesser extent to the stratum spinosum of the skin and the outer sheath of hair follicles. Concurrent MCMV infection in bone marrow transplants exacerbates the host-versus-graft reaction.

Temporal Regulation of Transcription

Viral gene knockouts have shown that either IE1 or IE0 is essential for viral replication and in the absence of this gene no viral infection is initiated. IE1 0 is an acidic domain transcriptional transactivator, similar to the herpesvirus VP16 protein and activates viral gene transcription by both enhancer-dependent and independent mechanisms. IE1 0 forms dimers that bind to the hr sequences which serve as the transcription enhancers. IE1 0 is also essential for the viral replication complex where it is believed to play the role of an origin binding protein. In support of this, it has been shown that a transcriptionally inactive OpMNPV IE1 is able to support transient viral DNA replication.

Progressive Amnestic Dementia Probable Alzheimers Disease

Other degenerative diseases that have been associated with a progressive amnestic dementia include diffuse Lewy body disease, Pick's disease, and focal neuronal atrophy (34,83-85). However, these pathological processes are much less common than Alzheimer's disease. In addition, there are a number of nondegenerative processes that have been associated with the amnestic syndrome. Most often, however, these are not progressive processes. They include anoxia, carbon monoxide poisoning, posterior cerebral artery strokes, anterior cerebral artery aneurysm with bleed or surgery, Korsakoff's syndrome, head trauma, and herpes encephalitis.

Pathology and Histopathology

Respiratory disease caused by EHV-1 and EHV-4 results in inflammation, congestion, and sometimes necrosis of the tissues of the upper respiratory tract. Extensive swelling of the nasal mucosa may occur and, in later stages, the lungs may become involved. One can find typical herpesvirus inclusion bodies in the nuclei of the respiratory epithelium. The respiratory infection can

Virus Transmission among Individuals

Shedding are virus yield (from the standpoint of the virus, the more shedding the better) and timeliness of yield (again, the earlier the shedding the better). Viruses that cause persistent infections often employ remarkable means to avoid host inflammatory and immune responses so as to continue shedding. For example, the epidemiologically important shedding of herpes simplex viruses 1 and 2 that perpetuates the viruses in populations requires recrudescence of persistent ganglionic infection, centrifugal viral genomic transit to peripheral nerve endings and productive infection of mucosal epithelium, all in the face of established host immunity.

Virus Replication

Although the latent state of EBV infection is most often associated with human disease, the replicative component of the virus life cycle is essential for the maintenance of EBV in the general population and therefore ultimately for the pathogenic potential of EBV. Unfortunately, delineation of the specific mechanisms through which mature EBV virions are produced has been hampered by the lack of cell lines that support EBV replication. Although some latently infected B cell lines can be induced to replicate EBV in response to chemical agents such as phorbol esters or by the crosslinking of cell-surface immunoglobulin molecules, the efficiency of induction is generally poor, in that only 20-30 of the treated cells, at best, will actually produce virus. Although epithelial cells are believed to be primary sites of EBV replication in vivo, attempts to establish epithelial cell lines readily infectable by EBV and which actively support virus replication have not been successful....

Host Range and Virus Propagation

Although the horse is the natural host of the equine herpesviruses, a variety of animals and tissue culture systems can be used to propagate the viruses. Regarding the major equine pathogen, EHV-1, experimental animals include Syrian hamsters and baby hamsters, chick embryos, baby mice and adult mice, and kittens. Primary tissue culture systems used to propagate EHV-1 include cells from a variety of equine tissues such as fetal lung, dermis, spleen and kidney, as well as cells from domestic cats, dogs, hamsters, rabbits,

Dl Particles and Persistent Infection

Altered outcomes of equine herpesvirus infections have been reported and include oncogenic transformation (EHV-1, EHV-2, EHV-3, and EHV-5) and persistent infection (EHV-1, EHV-2, and EHV-5). EHV-1 persistent infection and oncogenic transformation in vitro were shown to be mediated by virus preparations enriched for EHV-1 DI particles (DIPs). EHV-1 DI particles have been generated in vivo in the Syrian hamster model, and therefore DIPS may be generated in EHV-1 infection of the natural host. The DIPs are replication defective and require the standard virus as a helper. The majority of EHV-1 DNA sequences have been deleted from the genome of EHV-1 DIPs, such that sequences from three regions of the EHV-1 genome are conserved in the DIP genome. These three segments are (1) the L-terminus, including genes UL1, UL2 and the 3' portion of UL3-,

Ocular Complications of AIDS

Discrete areas of perivascular necrosis and hemorrhage are typical. (For color references see Color Plate 4.) Figure 4 Cytomegalovirus retinitis. Discrete areas of perivascular necrosis and hemorrhage are typical. (For color references see Color Plate 4.) Some ocular infections, including CMV retinitis (Fig. 4), Pneumocystis carinii, fungal and mycobacterial choroiditis, and microsporidial keratoconjunctivitis are seen almost exclusively in AIDS. Cytomegalovirus retinitis is a major cause of morbidity in AIDS patients. Other infections, such as toxoplasmosis retinochoroiditis, ocular syphilis, herpes zoster ophthalmicus, and molluscum conta-giosum of the eyelids are seen in immunocompetent as well as immunosuppressed individuals, but may be more severe and leave more profound deficits in HIV-infected patients. Herpes zoster ophthalmicus in young patients may be the first clinical clue to HIV infection. Acute retinal necrosis due to herpes simplex...

Immune Response Prevention and Control

CCV is sensitive to nucleoside analogues which inhibit the growth of higher vertebrate herpesviruses. In general, these compounds are phosphorylated by the virus, but not the cellular, thymidine kinase. Further steps in phosphorylation probably involve cellular enzymes. The triphosphate form then inhibits DNA replication by direct interaction with the DNA polymerase or by incorporation into nascent DNA. These compounds include the widely used antiherpe-tic drug acyclovir. Phosphonoacetate, which inhibits the DNA polymerase by mimicking pyrophosphate, is also inhibitory. It is doubtful, however, whether antiviral therapy will ever be practical for the treatment of CCV disease. Avoidance and containment of outbreaks presently involve the use of ostensibly virus-free breeding stock, as clean environmental conditions as practical, destruction of affected populations and disinfection of ponds. See also Antivirals Fish viruses Herpes simplex viruses (Herpesvirldae) General features,...

Red cell and platelet alloimmunization

Current practice is to perform maternal sera fetal Rh D genotyping in all Rh D negative alloimmunized women. In women who have a Rh D positive fetus maternal serum titres of Rh D antibodies are monitored and the patient referred for weekly MCA PSV monitoring using ultrasound once maternal serum levels reach 4 IU ml or if there has been a previously affected child. If the MCA PSV is above 1.5 21 a FBS under continuous ultrasound guidance is performed with immediate access to fetal blood analysis. If the fetus is anaemic it is transfused using maternally cross-matched O Rh negative, cytomegalovirus negative, irradiated, concentrated (haematocrit 70-90 ) blood. Weekly MCA PSV monitoring is continued and further FBS is performed if indicated on MCA PSV or at a 3-5 week interval to assess the rate of fall of haemoglobin. Women who have been transfused are usually delivered electively at 37-38 weeks and the neonate should go onto double phototherapy post-natally.

Mouse Embryos or Fetuses

Plasmids with a combination of highly efficient regulatory sequences that link, for instance, the 3-actin promoter and the cytomegalovirus enhancer (e.g., pCAGGS) (19) or duplicated 3-actin promoters linked with an IRES (Internal Ribosome Entry Site) sequence (e.g., pMIW) (20) yield the highest exogenous DNA expression.

Pathology Histopathology and Diagnosis

Rapid diagnosis of infection is therefore important for the initiation of appropriate preventive measures. The most commonly used method is the histopathologic examination of the lesion for the presence of cytoplasmic inclusion bodies. Since similar clinical signs involving the respiratory tract in chickens can be caused by infectious laryngotracheitis virus, rapid differential diagnosis of the disease becomes very important. Infection by this herpesvirus is characterized by the histologic demonstration of intranuclear inclusion bodies (Fig. 2D). On the other hand, poxvirus infections are diagnosed by histopathologic examination of the lesions for the presence of cytoplasmic inclusion bodies. These inclusions, which contain elementary bodies, can be observed under oil-immer-sion in stained smears of the lesions. In addition, viral particles exhibiting typical poxvirus morphology can be detected by electron microscopic examination of

Classificationtype Of Pathogen

The Epstein-Barr virus (EBV) belongs to the family of herpesviruses.1-1-1 With respect to morphology, EBV is hardly distinguishable from other family members. Based on pathogenesis, characteristics of replication, and host cell tropism, herpesviruses can be classified into three subfamilies alpha-, beta-, and gamma-herpesvirus. EBV belongs to the genus Lymphocrypto-virus of gamma-herpesviruses, which are characterized by a narrow host (cell) range and a slow rate of replication in cell culture.

Management Of Ebvassociated Diseases

Most cases of infectious mononucleosis do not require therapeutic intervention. In cases of clinically severe IM and life-threatening forms of SCAEBV, intravenous application of the nucleoside analog acyclovir or gancy-clovir may be necessary to reduce active viral replica-tion. 4 In addition, but not alone, antiphlogistic drugs to reduce the unspecific effects of the cellular immune response may be beneficial. Tonsillectomy is frequently used and was found to reduce symptoms of IM possibly

Mapping Viral Genomes

Among viruses that undergo intramolecular recombination, the probability of recombination occurring between two markers reflects the distance between them and recombination frequencies in adjacent intervals are approximately additive. Two-factor crosses are used to determine recombination frequencies between pairs of mutants for very close or distant markers three-factor crosses are used to resolve ambiguities. Recombination maps have been made for several large DNA viruses, notably herpes simplex virus, and for poliovirus. With the determination of nucleotide sequences the genetic markers of a number of viruses have been located on the relevant physical maps.

Enumeration of Absolute Cell Counts Using unit 68 Immunophenotypic Techniques

Enumeration of absolute CD4+ T lymphocyte number continues to be the hallmark laboratory test for staging HIV-infected patients. This is a critical surrogate marker for assessing immunodeficiency. The T cell subset value is an independent marker, yet it complements HIV plasma viral load data. As potent anti-HIV therapies are becoming more effective and complex, the CD4+ T cell levels for diagnostic prognostic staging of patients and therapeutic prophylactic intervention will continue to shift (Johnson et al., 1995 Lane, 1994). However, the utility of the CD4+ T cell count remains unchallenged and critical (Nicholson et al., 1994). The absolute and percent CD4+ T cell count is also of clinical relevance in other immunodeficiency conditions. These include solid-organ transplantation, the post-chemotherapy period, the recovery phase following bone marrow (or stem cell) transplants, therapy with purine nucleosides like 2-chlorodeoxyadenosine (cladribine) for hairy-cell leukemia,...

Virus Replication and Host Range

Naturally, HSV causes disease only in humans. However, it infects experimental animals such as hamsters, mice, rats, guinea pigs, rabbits and embryonated chicken eggs. The animal species, virus type, route of inoculation, and state of immune competence affect the outcome of infection. In the mouse, intracerebral, footpad, intranasal and intraperitoneal inoculations are used as models of human fatal neurological or visceral disease. Eye infection is used as a model of encephalitic and latent disease. Certain mouse strains (e.g. C57BL 6) exhibit natural resistance to HSV infection whereas newborn mice are particularly sensitive. HSV-1 infection of the skin was described in mice, rabbits and guinea pigs following skin abrasion or intradermal inoculation. HSV-2 mucosal infections have been studied in the mouse and the guinea pig. The best approximation of human recurrent cutaneous disease was achieved in the guinea pig. A wide variety of cell lines support HSV growth. Primary and...

Clinical Features of Infection

Most (70-90 ) childhood HSV-1 infections are asymptomatic, but they may be followed by subsequent recurrent episodes of symptomatic disease. In children 1-3 years of age, the major manifestion of HSV-1 infection is gingivostomatitis, a serious infection of the gums, tongue, mouth, lip, facial area and pharynx, often accompanied by high fever, malaise, myalgias, swollen gums, irritability, inability to cat and cervical lymphadenopathy. Later in life the major clinical manifestation of HSV-1 infection is an upper respiratory tract infection, generally pharyngitis. Reactivated HSV-1 is associated with mucosal ulcerations or lesions at the mucocutaneous junction of the lip, presenting as small vesicles that last 4-7 days and are known as herpes labialis, cold sores or fever blisters. Other HSV-1 skin diseases include primary herpes dermatitis (a generalized vesicular eruption), eczema herpeticum (usually a manifestation of a primary infection in which the skin is the portal of entry), and...

Host Immune Responses

Immune responses induced by HSV infection include an early nonspecific containment phase and a later HSV-specific effector phase. The relative contribution of these two phases differs according to the experimental model, the route of virus inoculation and the HSV serotype. Natural killer (NK) cells and or interferon (IFN) are the major factors involved in the nonspecific containment phase against HSV-1. Natural resistance of certain mouse strains to HSV infection was correlated with these factors. They act early in infection, thereby limiting HSV-1 growth and reducing the virus load. Intrinsic macrophage resistance, the mechanism of which is abortive infection, was implicated as the major determinant of the nonspecific containment phase against HSV-2. Lan-gerhans cells are involved in the control of cutaneous HSV infections. Various reports have incriminated or refuted the association of HLA with HSV infections. Al, A2, A9, BW16 and CW2 were associated with recurrent oral lesions Al,...

Prevention and Therapy

The ideal HSV therapy would both reduce the severity of the primary disease and prevent the establishment of latency. However, as there is no known agent that can prevent latency, the major goals for the treatment of HSV disease are to reduce (1) the time to resolution of clinical symptoms (2) the likelihood of complications and, should they occur, their severity and (3) the time of virus shedding and therefore the likelihood of transmission. Synthetic nucleoside analogues licensed for the treatment of HSV infections include idoxuridine for HSV keratitis and vidarabine for HSV encephalitis, neonatal herpes and HSV keratitis. Agents currently used for the treatment of HSV infections are acyclovir, available in topical, intravenous and oral formulations, famciclovir, valaciclovir, foscarnet and cidofovir, the latter two available in intravenous formulation for use in infections caused by acyclovir-resistant HSV. Acyclovir is phosphorylated by HSV thymidine kinase at a rate 106-fold...

Viral Replication Viral Entry

Other glycoproteins with one of at least three cellular surface proteins named the herpes virus entry mediator proteins (HVE - A, B, and C). HVEs are members of the TNF NGF family of proteins. Other cellular surface proteins may also function in a similar capacity as some cells lacking this receptor still allow efficient viral entry. The viral genome is accompanied into the nucleus by the aTIF protein (UL48) which functions in enhancing immediate early viral transcription via cellular transcription factors. The virion-associated host shut-off protein (f > s-UL41) appears to remain in the cytoplasm, where it causes the disaggregation of polyribosomes and degradation of cellular and viral RNA. Infecting DNA may remain associated with one or several structural components of the virion since it does not interact with cellular histones in a manner analogous to infecting papova-virus DNA.

Viral Replication Cytopathology

Classic features of the gross cytopathology of cells infected with HSV have long been used diagnostically. A very noticeable modification of the nucleus of the host cell with the condensation and margination of host chromatin at the nuclear membrane can be observed within a few hours after infection. This is followed by the accumulation of semicrystalline arrays of empty viral capsids in the nucleus leading to the formation of macroscopic inclusion bodies. Such nuclear changes are seen with most human and animal herpesvirus, and served for an early basis of classification of herpesviruses. Other 'classic' features of virus-induced cytopathology include extensive reduplication of the nuclear membrane as viral capsids associate with it, and the formation of extensive syncytia, which occurs with many (but not) all strains of the virus.

Latent Infection by HSV

LAT is controlled by the latency specific promoter, which has a number of regulatory elements important in neuronal expression over extended periods of time (Fig. 3). The establishment of latent herpesvirus infections can be essentially viewed as a passive phenomenon, as replication-defective virus can establish latent infections. This has been taken as support for the model that latency is just the result of the failure of the productive cascade, perhaps due to the specific population of transcription factors in the cell in which the latent infection is established. Some recent analysis of the functions of the proteins encoded by ORF-O and ORF-P in the long repeats suggests, however, that these proteins may serve to modulate immediate early gene expression. Viral genes may therefore function in optimizing the establishment of latent infections.

Immortalization of Macrophagelike Cells In Vitro

As herpesvirus sylvilagus induces a lymphoma-like disease, it infects both B and T cells in vivo, and these cells contain episomal viral genomes typically seen in cells immortalized with herpesviruses. Several laboratories investigated immortalization of lymphoid cells with the virus. All of the in vitro and in vivo attempts (published or unpublished) failed, except for a report on a 'macrophage-like' rabbit cell line established by in vitro infection of splenocytes with herpesvirus sylvilagus. This cell line contained integrated herpesvirus sylvilagus DNA. Lymphoid cell lines immortalized with other herpesviruses such as EBV or herpesvirus saimiri typically carry multiple copies of episomal viral genomes and integration seldom occurs. These basically negative results do not rule out the possibility that herpesvirus sylvilagus can immortalize lymphocytes for example, infected cells may require special growth factors and lymphokines for in vitro culturing. To resolve the issue of the...

Immune Response and Antiviral Drugs

The kinetics of virus-specific antibody development was determined using indirect fluorescent antibody (IFA) technique on herpesvirus sylvilagus-infected newborn cottontail rabbit kidney (NCRK) cells. Antibodies were detected by the IFA test as early as 5 days after experimental infection. All animals seroconverted to herpesvirus sylvilagus by 10 days after infection and antibodies could be observed in serum dilutions of 1 2000 or higher. No extensive studies on antiviral drugs have been reported. Replication of herpesvirus sylvilagus is significantly inhibited by phosphonoacetate (PAA) and phosphonoformate (PFA). These drugs also inhibit most other herpesviruses.

Host Range and Viral Propagation

Gammaberpesuirinae, in general, have a host range limited to the family or order of the natural host. Cultivation of both herpesvirus papio and herpesvirus pan is restricted to B cell lymphocytes. Originally the baboon isolates were obtained by cultivation of bone marrow and splenic cells from a lymphomatous hamadryas baboon. Cells were grown in RPMI 1640 supplemented with 20 heat-inactivated bovine embryo serum and maintained at 37 C in a 5 C02 atmosphere. The appearance of cell clumps along with enhanced metabolic activity and cell growth are the criteria of successful cell cultivation. Viral presence is determined by observing typical herpeslike viral particles within the cells and or the transformation (immortalization) of infected lymphocytes. Serological tests for the presence of viral (V) and soluble (S) antigens, using known positive sera, confirm the presence of virus. Host range of herpesvirus papio and herpesvirus pan may be determined by the presence of transformed B cells...

Serologic Relationships and Variability

Lymphotropic herpesviruses papio and pan are anti-genically closely related to isolates obtained from the gorilla (herpesvirus gorilla) and orangutan (herpesvirus pongo), as well as other EBV-like isolates, although there are antigenic differences. As a group, they all share DNA homology and antigenicity as well as other biologic activities with EBV. EBV and the EBV-like viruses all have associated antigens VCA, EA, membrane antigen (MA) and EBNA. Herpesvirus papio and herpesvirus pan will cross react with EBV when sera are tested for anti-VCA, anti-EA and anti-MA. However, the baboon virus does not crossreact with EBV when tested for anti-EBNA. Herpesvirus papio does not induce nuclear antigens in infected cells, as does EBV, but does produce an analogous antigen. All three viruses It is apparent that the more recently described HVP-2 isolates, while closely related to SA8, are distinct entities. Eberle et al even suggest that the recognized baboon infections were due to HVP-2 rather...

Transmission and Tissue Tropism

Transmitting vehicles of herpesviruses may include such materials as respiratory secretions, blood, saliva, contact with infected lesions and sexual intercourse. Both herpesvirus papio and herpesvirus pan are readily transmitted in nature to their respective natural host animals via respiratory secretions. Experimental production of tumors, however, has been limited to the inoculation of marmosets with large numbers of herpesvirus papio-producing baboon cells. Cotton top marmosets develop an acute, widely disseminated lymphoproliferative disease. In view of the possible need for another virus (STLV-1, other ) to help in the production of baboon tumors, it would be of interest to determine whether herpesvirus papio alone is responsible for tumor production in marmosets. Although herpesvirus pan is not known to cause disease, experimental infection occurs in various species of animals, as measured by antibody development. Lymphocyte infection by herpesvirus papio or herpesvirus pan is...

Properties of the Genome

The genomes of HHV-6 and HHV-7 are linear double-stranded DNA molecules of approximately 159 kb and 145 kb, respectively. The gene organization of each is illustrated in Fig. 1. The complete genomic sequences were determined for HHV-6A strain U1102 and HHV-7 strain JI, and partial sequences were reported for other strains, including HHV-6B strain HST.HHV-6A and HHV-6B are very similar genetically because their nucleotide sequences differ by 4-10 between the variants, depending on the gene being compared. This similarity, which is higher than that for any other independently recognized herpesvirus species, led to the decision to adopt the variants A and B nomenclature, rather than name the variants as distinct species. Sequence comparison among herpesvirus species revealed the highest conservation of genetic content and encoded protein products between HHV-6 and HHV-7, ranging from 41 to 75 amino acid sequence identity for the core herpesvirus gene products. HHV-6A strain U1102 DNA...

Taxonomy and Classification Host Range

HVS-2, saimiriine herpesvirus 2, is classified as a gammaherpesvirus, based upon virus molecular organization and growth properties, including cell trop-ism. This agent is not to be confused with saimiriine herpesvirus 1 (HVS-1) which is an alphaherpesvirus in marmosets. Similar to other herpesviruses, HVS-2 can establish latency within the natural hosts' target cells. HVS-2 DNA sequence analysis has demonstrated that, genetically, this virus is organized most like Epstein Barr virus (EBV), when compared with viruses within the broad subfamilies of alpha-, beta-, and gammaherpesviruses. However, distinctive features are apparent, including overall arrangement of the genome of the virus. Because of these differences, along with the relatively distant relationships of each of these New World monkey viruses to EBV, HVS-2 is considered a gamma-2 herpesvirus within the sub Interestingly, gamma-2 herpesviruses are T lymphocyte tropic, as opposed to gamma-1 herpesviruses which are B...

Growth and Propagation of Virus in the Laboratory

Each of these New World monkey herpesviruses has a morphology consistent among the agents classified as herpesviruses. Nucleocapsids are formed in the nuclei of infected cells and are approximately 100 nm in diameter, with dense centers. The mature, enveloped particles are slightly larger and located in cytoplasmic vacuoles of infected cells. Glycosylation of envelope proteins occurs within the endoplasmic reticulum and Golgi apparatus to form mature virions. HVS-2 grows well in primary cells derived from New World monkeys but less efficiently in those derived from Old World monkeys, while HVA-2 grows well in a variety of epithelial and fibroblast cells from New World monkeys as well as African green monkeys (Old World monkeys). The spider monkey virus generally replicates to a lower titer in cell culture than the squirrel monkey herpesvirus. In vitro, HVA-2 is capable of immortalizing a variety of lymphoid cells from New World primates, whereas there has been more difficulty using...

Summary and Future Perspectives

Each of these Rhadinovirus members of the family Herpesviridae has immense potential for use as a tool to transform immortalize target cells of interest, particularly with respect to studies of human immunodeficiency virus (HIV) and AIDS. Gene-specific transformation or immortalization of cells is also possible, reducing the input of the nonessential viral genes against the background of the transfected cells. Transformation-associated genes represent a novel class of viral oncogenes which warrant further investigation. Furthermore, each of these virus host systems continues to offer investigators a unique and invaluable avenue for epidemiological studies of virus transmission in nature, both within natural and foreign hosts. Last, but not least, due to the capacity of these viruses for carrying large amounts of DNA inserts, the use of HVS-2 and HVA-2 as novel gene See also Herpesviruses - baboon and chimpanzee (Herpesviridae) Herpes simplex viruses (Herpesviridae)-. General features,...

Methylation Patterns of Latent HSV1 Genomes In Vitro and In Vivo

In a pioneering study, Youssoufian et al. investigated a major epigenetic regulatory mechanism, cytosine methylation (a heritable form of DNA modification) using cells either carrying latent herpes simplex virus type 1 (HSV-1) genomes or undergoing productive infection (Youssoufian et al. 1982). Digestion with cytosine methylation-sensitive and cytosine methylation-resistant restriction enzyme pairs followed by Southern blotting revealed that the latent HSV-1 genomes were highly methylated in cells of a persistently infected lymphoblastoid T cell line (CEM) treated with concanavalin A. In contrast, only unmethylated viral genomes could be detected during productive infection in this reversible in vitro model of viral latency. This study suggested that DNA methylation might play a role in the maintenance of HSV-1 latency.

Properties of the Viral Proteins

The nonstructural Npro is a protease with autopro-teolytic activity it has no counterpart in flaviviruses. The nucleocapsid protein (C) precedes the three envelope glycoproteins. The Erns protein (formerly called gp42) forms a disulfide-linked homodimer. The mechanisms by which it is associated with the virion is unknown it is also secreted from infected cells. A remarkable feature of Erns is its RNase activity, which is unique among viruses. The function of this enzymatic activity is as yet unclear. The Erns protein exhibits a strong immunosuppressive effect in vitro, and elimination of the RNase activity results in a cytopathogenic virus (HCV is normally noncyto-pathogenic). The El protein (gp31) is, as a disulfide-linked E1-E2 heterodimer, present in the viral envelope, and the E2 (gp53) as a disulfide-linked homodimer and as a heterodimer with El. The E2 protein is composed of at least four antigenic domains, three of which give rise to neutralizing antibodies. The E2 protein...

Resistance Genes Constitutively Expressed in Target Cells

Two resistance genes listed in Table 1 are constitutively expressed in target cells. These are the H-2D gene that controls resistance to the lethal effects of mouse cytomegalovirus (MCMV) infection and the Hv-2 locus that regulates susceptibility to acute mortality caused by mouse hepatitis virus type 4 (MHV4). Inbred strains of mice that carry the MHC H-2k haplotype are among the most resistant to acute mortality caused by MCMV, a herpesvirus. Mice that carry the H-2d or H-2b haplotypes are 10 times more susceptible to lethal cytomegalovirus infection and permit significantly more virus replication than mice of the same genetic background that carry the H-2k haplotype. This difference is determined by the class I gene, H-2D. Products of class I MHC genes are important in cellular immune responses. Class I antigens are expressed by a wide variety of cells and serve as recognition molecules for specific classes of T cells. In the case of cytomegalovirus infection, however, the role of...

Xcytokine Receptors As Viral Proteins

Interestingly, the genome of the human herpes virus 8 (HHV8), which is associated with Kaposi Sarcoma and Castleman Disease, encodes a cytokine with significant homology to human IL-6. This viral IL-6 (vIL-6) directly binds to gp130 with a stochiometry of two vIL-6 molecules and two gp130 molecules 43 . Therefore, vIL-6 functionally substitutes for the complex of IL-6 and IL-6R (in membrane-bound or soluble forms). As gp130 is ubiquitously expressed, vIL-6 is able to stimulate virtually all cells of the body, which might help to explain the role of vIL-6 in the pathophysiology of HHV8 44 .

Role of the Virus in AIDS Pathogenesis

Acquired Immune Deficiency Syndrome (AIDS, SIDA in French and Spanish-speaking countries) was defined in the early 1980s, biologically by a profound defect of cellular immunity associated with a deep shortage of CD4+ T lymphocytes and clinically by the occurrence of opportunistic infections and cancers. In Western countries, the most frequent infections are those of the lungs by Pneumocystis carinii and of the brain by toxoplasmas, followed by visceral and retinal infections by cytomegalovirus (CMV). Tuberculosis is frequent in tropical areas (Africa, Asia, South America). Among cancers, the most frequent are disseminated and aggressive Kaposi's sarcoma caused by human herpesvirus 8 (HHV-8) and B-lymphomas, often caused by Epstein Barr virus (EBV).

Pathways of the CNS Invasion

Viruses have been shown to enter the nervous system both along nerves and from the blood. The first experimental studies of viral invasion employed rabies, herpes simplex, or polioviruses, all of which, under experimental circumstances, can penetrate the nervous system along peripheral nerves. The precise mechanisms of neural spread remained a mystery for many years, since it was thought that the axoplasm slowly oozed in an anterograde direction. It was proposed that virus might move in perivascular lymphatics, by ascending infection of the supportive cells within the peripheral nerve, or even by replication in axons, a speculation that is now untenable because of the observed lack of ribosomes or protein synthesis within axons. In the 1960s active anterograde and retrograde axon transport systems were found. Viruses or other particles can be taken up in vesicles at the nerve terminals and transported to the cell body ofthe sensory or motor neuron (Figure 1). This neural route of...