Hepatitis Ebook

Alternative Hepatitis C Treatments

The therapeutic goals of Natural treatment for Hepatitis C are as follows: Decrease iral load Normalize liver enzyme levels. Enhance/regulate immune system function. Strengthen and promote healthy liver function. Protect the liver, prevent further damage. Virological response; i.e. viral clearance, viral reduction or elimination of the virus. Starve the virus by limiting levels of iron. Optimizing cellular levels of glutathione in the body, making detoxification of the liver possible and enhancing the immune system. Stimulate regeneration of the damaged liver cells. Use of antioxidants to combat the effects of free-radicals generated by the virus. Reduce inflammation. Slow viral replication. Replace all of the inflammation-damaged liver cells. Regulate immune function/prevent auto-immune problems. Cancer preventative measures. Reverse fibrosis to prevent and improve cirrhosis

Alternative Hepatitis C Treatments Overview


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Hepatitis Introduction

Hepatitis is the inflammation of the liver usually caused by a virus. Four viruses that may cause it are hepatitis A (HAV), hepatitis B (HBV), hepatitis D (HDV) and hepatitis non-A, non-B (NANB). Most common of the types found in children is hepatitis A which is transmitted by the fecal-oral route. The incidence in children is increased in those living in crowded housing. The disorder is usually self-limiting with resolution within 2 to 3 months or may develop into chronic hepatitis. Symptomology varies with severity of the disease.

Progress On New Hepatitis C Virus Targets Ns2 And Ns5a

Hepatitis C virus (HCV) is a major global health problem, affecting about 170 million people worldwide. Chronic infection can lead to cirrhosis and liver cancer. The replication machine of HCV is a multi-subunit membrane associated complex, consisting of nonstructural proteins (NS2-5B), which replicate the viral RNA genome. The structures of NS5A and NS2 were recently determined. NS5A is an essential replicase component that also modulates numerous cellular processes ranging from innate immunity to cell growth and survival. The structure reveals a novel protein fold, a new zinc coordination motif, a disulfide bond and a dimer interface. Analysis of molecular surfaces suggests the location of the membrane interaction surface of NS5A, as well as hypothetical protein and RNA binding sites. NS2 is one of two virally encoded proteases that are required for processing the viral polyprotein into the mature nonstructural proteins. NS2 is a dimeric cysteine protease with two...

Differentially Expressed Genes Associated With Hepatitis B Virus HBx and MHBs Protein Function in Hepatocellular

HBx and MHBs' products from hepatitis B virus-DNA (HBV-DNA), which become transcriptional transactivators of cellular and viral genes, are known to play causative roles in the development of hepatocellular carcinoma (HCC). However, the biomolecular mechanism(s) for their roles in hepatocarcinogenesis in vivo remain poorly understood. To identify authentic cellular genes involved in HBx and MHBsl-transactivated carcinogenesis, we used mRNA differential display polymerase chain reaction (DD-PCR). We examined HBx and MHBs-positive or -negative HCC, which had chromosomally integrated HBV DNA, vs nontumor tissues, respectively, and differentially expressed genes in either type of HCC were identified and compared with each other. Using 240 different combinations of three one-base anchored oligo-dT primers and 80 arbitrary 13mers, 16 genes were differentially expressed in the HBx and MHBs-positive HCC including Ro RNA hY1, glutamine synthetase, factor H homologue 3' end, voltage-dependent...

The Hepatitis B Vaccines

The hepatitis B vaccines contain HBsAg and are given via an intramuscular injection to stimulate a protective anti-HBs response. The first-generation (so-called 'plasma derived') vaccine was produced by purifying HBsAg from donated blood. Despite some worries that blood-borne viruses (particularly human immunodeficiency virus (HIV)) potentially might contaminate particular batches, this method of vaccine production is safe provided that manufacturing protocols, including steps that inactivate potential infec-tivity, are adhered to strictly. Even today, plasma-derived vaccines constitute the majority of doses given worldwide. Currently, most doses of hepatitis B vaccine given in the West are produced by expression of HBsAg in yeast (Saccharomyces cerevisiae), and several vaccines based on expression in mammalian cells also have been licensed. Most countries worldwide have now introduced universal immunization of infants. Although the vaccine may be incorporated into the Expanded...

HCV Replication Cycle

HCV infection starts by binding the envelope glycoprotein E1 E2 complex on the surface of the virus particle to its cognate receptor(s) presumably leading to clathrin-mediated endocytosis and a subsequent fusion step from within an acidic endosomal compartment (Figure 3). Cellular factors implicated in virus binding and entry are glycosaminoglycans, scavenger receptor class B type 1 (SR-B1), CD81, and low-density lipoprotein (LDL) receptor. However, for most of these factors, the precise role is not well understood and one or several additional factors may be required for productive entry. Upon release of the RNA genome, the polyprotein is expressed by IRES-dependent translation occurring at the rough endoplasmic reticulum (rER) where host cell signal peptidases, signal peptide peptidases, and viral proteases catalyze polyprotein cleavage.

Treatment of Chronic Hepatitis B

Prior to the introduction of specific antiviral therapeutics, persistent HBV infection was treated with interferon, with mixed success. In some studies, up to one-third of treated individuals cleared the virus, but the treatment was rather less successful in certain populations, particularly individuals from the Far East. Interferon seems to work by modulating the immune response of the host, rather than a direct antiviral effect, and was found to be most successful in individuals who had evidence of hepatitis or, in other words, already were mounting a cellular immune response to the virus. Figure 5 Expression of the HBV core ORF. The pregenomic RNA is translated from the second initiation codon in the ORF to yield HBcAg. The precore RNA is translated from the upstream initiation codon to p25, which is processed to HBeAg. The arrow indicates the position of the most common precore mutation, changing a tryptophan to a termination codon. Reproduced from Harrison TJ (2006) Hepatitis B...

The Amplicor HCV Monitor 20 and Cobas Amplicor HCV Monitor 20 Test Roche Diagnostic Systems

Based on reverse transcription polymerase chain reaction (RT-PCR), the Amplicor HCV Monitor test (Roche Diagnostic Systems) was developed. 5 Recently, an improved version 2.0 was introduced, which achieved an equivalent quantitation of each genotype over the quantitative range (5 x 102 to 5 x 105 copies of RNA mL). 6,7 HCV RNA is extracted from plasma by chaotropic salt and is then precipitated by isopropanol. Both RT and PCR of RNA are accomplished in one tube using the recombinant thermostable DNA polymerase (rTth), which offers both reverse transcriptase activity, forming a cDNA from the RNA target sequence of the 5' UTR, and polymerase activity for amplification of the cDNA under appropriate conditions. An internal quantification standard shows the same primer-binding sites as the target but with a changed internal sequence, which allows binding to special detection probes. This allows quantification after a series of dilutions at the end of the assay. To meet the needs of routine...

Hcv Rna Quantitation

Quantitation of HCV RNA by bDNA technology is possible with the commercial VERSANT HCV RNA 3.0 assay. The performance characteristics of this test were established in our laboratory during the so-called ''beta trials'' before licensing and are given in Table 1. 4 Our findings were essentially confirmed by other studies, 11,12 and showed that the assay, from an analytical point of view, can be used as a routine tool for HCV RNA quantitation in clinical laboratory settings. Table 1 Analytical performance characteristics of VERSANT HCV RNA 3.0 assay Table 1 Analytical performance characteristics of VERSANT HCV RNA 3.0 assay


Of hepatitis are self-limiting and resolve without complications. Hospitalization is required only when symptoms are severe, persistent, or debilitating. Approximately 20 of acute hepatitis B and 50 of hepatitis C cases progress to a chronic state. In Americans, 5 to 10 of patients with hepatitis have hepatitis B virus (HBV) infections. In third world countries, the rates are much higher. The most serious complication of hepatitis is fulminant hepatitis, which occurs in approximately 1 of all patients and leads to liver failure and hepatic encephalopathy and, in some, to death within 2 weeks of onset. Other complications include a syndrome that resembles serum sickness (muscle and joint pain, rash, angioedema), as well as cirrhosis, pancreatitis, myocarditis, aplastic anemia, or peripheral neuropathy.

Hepatitis B

Hepatitis B, or serum hepatitis, is spread mainly through contaminated blood, often from unsterilized needles shared by drug users or used for tattoos or ear or body piercing. The virus can also be transmitted sexually. Over 100,000 people are infected yearly in the United States, but this number is decreasing due to the recent introduction of a vaccine. In addition to the initial disease, which is more severe than hepatitis A (more liver damage and fatality rate of 10 ), those infected are at higher risk of liver cancer.

Hcv Ns5a

NS5A is an active component of the HCV RNA replicase, a pivotal regulator of replication, and a modulator of numerous cellular processes spanning from innate immunity to apoptosis and disregulated cell growth.29'41 It exists as a serine phosphoprotein present in hypo- (56 kDa) and hyper-phosphorylated (58 kDa) forms. An amphipathic a-helix at its N terminus promotes association with cellular membranes.4'8'32 Following this helix, NS5A is organized into three domains (Fig. 2A)40 The N-terminal domain (domain I) coordinates a single zinc atom per protein molecule.40 Mutations disrupting either the membrane anchor8,32 or zinc binding40 are lethal for HCV RNA replication. NS5A interacts with other viral components of the replicase7 and has been shown to modulate NS5B polymerase activity in vitro.37'38 NS5A domain II and the region connecting domain I and II are hotspots for adaptive mutations that can enhance replication in cell culture by more that 10,000-fold.2'26 Such highly adaptive...

Hepatitis D Virus

HDV merits a brief mention because of its particular association with HBV. As noted above, a novel antigen, termed delta, was discovered in patients with hepatitis B and this turned out to be the nucleocapsid protein of HDV. The HDV genome is a single-stranded circle of RNA that resembles the viroids and virusoids of plants it is believed to be replicated by the host RNA polymerase II, with cleavage and rejoining of the circle mediated by a ribozyme activity. Unlike the viroids and virusoids, HDV was first discovered in Italy and is found in the Mediterranean area, reportedly with a declining prevalence, and also in the Far East and South America. The virus may be acquired as a coinfection with HBV or by super-infection of someone already HBsAg-positive. In both cases, disease may be more severe than with HBV alone, and chronic delta hepatitis may progress to cirrhosis more frequently, and more rapidly, than chronic hepatitis B. The hepatitis B vaccine also protects against...

Hepatitis Viruses

Hepatitis A virus or hepatitis delta and epsilon viruses have been uncommon sources of hepatitis in transplant patients. In contrast, infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) have been frequent. Transplant patients may be more susceptible to the complications of HBV and HCV infection, but the uncertainty regarding epidemiology and pathogenesis of these infections complicates decisions regarding the suitability of patients with hepatitis for transplant. There have been many impediments to an understanding of the consequence of hepatitis. Until the recent development of the anti-HCV assay, the course of patients with HCV infection could not be distinguished from the course of patients with other hepatic abnormalities. Even though patients with HCV can now be identified, the current assay is insensitive. Meanwhile, assays for HBV infection, long considered sensitive and specific, do not adequately detail the potential for HBV reactivation and infectivity. Thus,...

HCVHost Interaction

Several cellular proteins appear to contribute to HCV replication. For example, the ubiquitously expressed human vesicle-associated membrane protein-associated protein A (VAP-A) and its isoform VAP-B were identified as interaction partners of NS5A and NS5B. NS5A hyperphosphorylation seems to disrupt the VAP-A association and thereby negatively regulates HCV RNA replication. It is thought that VAP-A directs HCV nonstructural proteins to cholesterol-rich, detergent-resistant membranes, which are the presumed sites of HCV RNA replication. Another host cell factor interacting with NS5A is FBL-2 belonging to the family of proteins that contain an F box and multiple leucine-rich repeats. FBL-2 is modified by geranylgeranylation which is important for NS5A interaction. FBL-2 appears to be required for HCV RNA replication. Likewise, Cyclophilin B (CyPB), a cellular protein interacting with the NS5B RdRp, seems to contribute to replication of genotype 1 isolates by promoting RNA-binding...

Prevention and Therapy

In the veterinary practice, dog vaccination schedules all over the world invariably include a live or killed CAdV-1 component against dog hepatitis. Inactivated vaccine for horses against equine adenoviruses has been prepared in Australia. In farm animals, inactivated bivalent vaccines (containing one mastadenovirus and one atadenovirus) have been in use in several countries for

Viruses Associated with Inhibition or Suppression of Apoptosis

Death receptors Hepatitis B virus (pX) Hepatitis C virus core Hepadnavirus Hepatitis B virus (HBV) encodes pX that interacts with p53, interfering with DNA binding and transcriptional activation. pX is also an HBV viral oncogene involved in HBV-induced hepatocellular carcinomas, perhaps by blocking p53-activated Flavivirus The hepatitis c virus (HCV) viral core protein, which seems to be a transcriptional regulator, suppresses apoptosis through the CPP32 cysteine protease, but the mechanism is not known. The core protein seems to be involved in the pathogenesis of HCV.

How is the harm of a treatment documented

Occasionally, drugs may have serious adverse effects such as allergic reactions, hepatitis, cardiac arrhythmias and gastric ulcer. Despite this, attributing an adverse event to a specific treatment can sometimes be difficult, particularly when the event is rare, unexpected, or appears a long time after the start of treatment. It can also be difficult to recognize an adverse effect when it may occur as part of the natural history of the underlying condition. These challenges are discussed in Chapter 4.

Transmission and Tissue Tropism

Transmission in outbreaks in daycare centers and nursing homes. Infection may also occur via contaminated water or foods, particularly shellfish. Most human and animal astroviruses are associated with symptoms of gastroenteritis, and replication has been documented in the gastrointestinal tract. A noteworthy exception is duck hepatitis virus which has been detected by EM in the livers of animals with histologic evidence of hepatitis.

HIV and Kidney Disease

Many of the causes of acute renal failure in HIV-infected patients are the same as for HIV-negative individuals, with a similar incidence of 5.9 cases per 100 patient-years. It is associated with a nearly sixfold increased risk of in-hospital mortality in HIV-infected patients. Factors associated with increased incidence in HIV-infected patients include advanced stage of HIV disease, exposure to antiretroviral therapy, and co-infection with hepatitis C virus. Pre-renal causes include hypovolemia, hypotension, or hypoalbu-minemia. Intrinsic kidney diseases including acute tubular Renal disease associated with HAART In some cases, HAART can reverse or at least control nephropathy associated with HIV infection. However, many antiretroviral medications have been associated with renal toxicity including acute and chronic renal disease. The newer antiretroviral agents commonly in use are associated with few side effects. Adefovir was the first NRTI shown to have variable antiretroviral...

Epidemiology And Clinical Features

Currently, eight serotypes of human astrovirus are recognized (HuAst 1-8) based upon epitopes on ORF2. It is also possible to genotype HuAst by examination of sequence data of ORF1a, ORF1b, and the 5' end of ORF2, 12 and genotypes equivalent to the eight serotypes have been defined. Recently, evidence for a novel recombinant HuAst has been uncovered. 13 There is no cross-reactivity between the HuAst serotypes, and immunity to one does not give immunity to the others. Astroviruses have been detected in diarrheic animals and as a cause of hepatitis in ducks. Phylogenetic analyses of a large collection of sequences from a variety of astroviruses showed that all the HuAst clustered together separate from the nonhuman strains however, the branching order of the astroviruses was the opposite of their host species indicating the possibility of cross-

Bio Robot Workstations

For the extraction of hepatitis C virus RNA, it was shown that it is possible to achieve a detection level of 12.8 IU mL (95 confidence). Cross-contamination studies have confirmed that the use of the BioRobot 9604 does not pose a detectable contamination risk. 2 For hepatitis B virus detection, Mitsunaga et al. describe that it was possible to quantify DNA in all samples extracted by the BioRobot 9604 which contained more than 500 genome equivalents mL. Extraction of 96 samples could be completed within 2 hr. 3

Preconceptual counselling in the lowrisk setting

Most women in developed countries will be immune, and therefore particular care must be taken to screen immigrant groups. HIV and hepatitis are not normally checked other than in women undergoing fertility treatment or in immunocom-promised groups, though a case can be made for such a check prior to conception. Hepatitis C and varicella may be checked selectively.

Taxonomy and Classification

Early structure analyses of BVDV and CSFV indicated a virion architecture similar to the classic toga-viruses. Since there was no apparent insect vector for these viruses, the term 'nonarthropod-borne toga-viruses' was created to include BVDV, BDV, CSFV, equine arteritis virus, lactate dehydrogenase virus and rubella. With the establishment of the antigenic relationship of BVDV, BDV and CSFV, a new genus, Pestivirus, was created within the family Togaviridae in 1982. Data on the genomic structure of the pesti-viruses indicated a closer relationship to viruses such as yellow fever virus and West Nile virus, and in 1991 the pestiviruses were reclassified in the genus Pestivirus within the Flaviviridae family. Yellow fever virus is in the genus Flavivirus. The hepatitis C group of viruses are also included within this family under the genus 'Hepatitis C-like viruses'.

Distribution Epidemiology and Transmission

In 1997, the identification of TTV DNA in the blood of Japanese patients with hepatitis of unknown etiology was the starting point of the research on this new group of viruses. Despite its initial identification in populations with liver disorders, further epidemiological studies not only identified the virus in populations with parenteral risk exposure, including intravenous drug users, hemophiliacs, or HIV infected patients, but also in populations without proven pathology like blood donors. It was also clearly demonstrated that TTV is distributed worldwide, as the virus was detected in rural or urban populations in Africa, Americas, Asia, Europe, and Oceania.

Clinical Significance

Historical presentation of TTV as associated with elevated transaminase levels in post-transfusion hepatitis of unknown etiology suggested that the virus was able to induce non-A G hepatitis. Therefore, TTV was suspected as a possible cause of some forms of acute and chronic hepatitis and fulminant liver failure, and could be involved in liver diseases. The identification of TTV in the general population seems to refute this interpretation and led to the suggestion that the virus may cause only occasional liver injury, either by the implication of hepa-totropic variants or by the presence of host determinants enhancing the pathogenicity of TTV.

Liver Regeneration And Inflammatory Mediators

Liver regeneration requires the activity of multiple signaling pathways, assuring the synchronized proliferation of liver cells, protection from apoptotic signals, remodeling of extracellular matrix (ECM), and restoration of lobular architec-ture7. The initiation of regeneration through PHx is associated with minimal injury therefore, an obvious inflammatory reaction that includes a significant inflammatory infiltrate is not seen in the liver parenchyma under these circumstances. However, elevated levels of acute-phase proteins in the blood, activation of liver macrophages, and release of cytokines that are involved in regulation of inflammatory responses to various pathogens suggest that PHx does initiate an inflammatory reaction4. Unlike PHx, injection of CCl4 results in an inflammatory infiltrate in the liver in response to necrosis. In this model, regeneration is associated with significant tissue injury and an inflammatory response not seen after PHx. Though cell death and the...

Classification and Properties

Although superficially resembling picornaviruses, with which they were once classified, in some of their properties the distinctive properties led to the creation of the family Caliciviridae. The family Caliciviridae contains four genera two of which contain members that are the subject of this entry one of which includes the related viruses of vesicular exanthema virus and San Miguel sea lion virus as well as feline calicivirus (Vesiculovirus genus) and the second the related viruses that cause rabbit hemorrhagic disease and European brown hare syndrome (Lagovirus genus). Two other genera include Norwalk ('Norwalk-like viruses') and Sapporo viruses ('Sapporo-like viruses') that cause diarrhea in humans. Hepatitis E virus ('hepatitis-E-like viruses' genus) and a related virus isolated from pigs in midwestern USA have not been assigned to a family. Probable caliciviruses have also been recovered from monkeys, cattle, mink, swine (in addition to vesicular exanthema virus), dog, rabbit,...

Infectious Disease Applications

The development and ongoing improvement of bDNA technology during the past decade was mainly driven by the increasing demand for quantitation of nucleic acids in clinical virology. Understanding the natural history and pathogenesis of chronic viral infections caused, for instance, by hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) has been greatly supported by accurate determinations of viral load. Consequently, measurements of HBV DNA, HCV RNA, and HIV RNA are extensively used in today's clinical practice to monitor the efficacy of antiviral treatment, predict the outcome of therapeutic strategies,

Expansion into Therapies for Other Viruses

A spin-off from this work with HIV has led to inhibitors of other families of viruses, particularly hepatitis B virus (HBV). Lamivudine and adefovir have become the treatments of choice for HBV. Meanwhile, there seemed to be progress discovering compounds active against picorna-viruses (which include rhinoviruses causing the common cold). These compounds bind into a pocket within the viral capsid. The best example is pleconaril although unacceptable side effects stopped its development. However, the viruses quickly became resistant and some strains even became dependent on the 'antiviral' compound. Therefore, this approach has not resulted in any clinically useful drugs. Once the structure of influenza virus neuraminidase was known, new inhibitors of influenza viruses were discovered. Recent advances with replication systems for hepatitis C virus (HCV) have allowed the discovery of anti-HCV compounds. Currently, the threat of bio-terrorism has prompted the successful search for drugs...

Gender Ethnicracial And Life Span Considerations

Blood bank protocols have lowered the risk of human immunodeficiency virus (HIV) transmission from more than 25,000 cases before 1985 to a risk of 1 in 50,000 to approximately 1 in 150,000 currently. In spite of the decreased risk, many patients worry about contracting HIV when they need blood products. In reality, the risk of hepatitis B and C is much higher. If a blood transfusion reaction occurs, the fears and anxieties are compounded and may warrant specific interventions.

Important Classes of Antiviral Targets and Compounds

Mimetics were designed specifically to target HIV protease. The resulting compounds, several of which are now standard HIV drugs, are among the most active antiviral compounds known and inhibit HIV in the nanomolar range. Like other HIV antivirals, drug-resistant mutants arise and so the compounds are used in combination with reverse transcriptase inhibitors. Other families of viruses encode proteases except for HCV, the search for effective inhibitors has yielded few useful 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.

Discharge And Home Healthcare Guidelines

Explain that the patient should notify the primary healthcare provider if she or he develops any discomfort in the first few months after transfusion. Attributing these signs to specific diseases may make the patient unnecessarily anxious, but the patient should know to notify the healthcare provider for anorexia, malaise, nausea, vomiting, concentrated urine, and jaundice within 4 to 6 weeks after transfusion (hepatitis B) jaundice, lethargy, and irritability with a milder intensity than that of hepatitis B (hepatitis C) or flulike symptoms (HIV infection).

Antiviral Combination Therapy

The problem of antiviral resistance led directly to the introduction of antiviral combination therapy as a crucial feature to control chronic virus infections, notably those caused by HIV and probably will be with HBV and HCV. Initially, there was much opposition to the introduction of antiviral combinations, probably best explained by an underlying fear of enhanced toxicity this was the problem that dominated the early phase of HIV therapy but eased as newer, better tolerated drugs became available. HIV presented a new urgency very high levels of HIV genome RNA turnover in the patient and the high mutation rate in the HIV genome meant that antiviral resistance inevitably led to the failure of monotherapies. The concept of genetic barrier was developed at this time. The aim is to create the highest possible genetic barrier and stop all virus replication so that the virus has no chance to overcome that barrier by mutation. This ultimately led to HAART involving the use of triple and...

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.

Regulatory Viral RNAs and RNABinding Proteins

Early recognition of several viruses is mediated by PRRs and results in the activation of interferon and NF-kB. Recent advances have been made in this area through the discovery of RIG-I and Mda5 as well as their downstream signaling partner, the CARD-containing mito-chondrial antiviral signaling protein (MAVS). The protease NS3 4A from the flavivirus hepatitis C virus (HCV) cleaves and inactivates MAVS, thereby short-circuiting virus recognition and signaling through the CARD. Meanwhile, the same protease also cleaves the TIR domain-containing adaptor-inducing IFN-b (TRIF) and short-circuits TLR signaling as well. Vaccinia virus uses a clever trick to dampen TLR signaling A46R contains a TIR domain to sequester TRIF away from TLR3, thus preventing the recognition of viral antigens. Other virus factors modulate RIG-I and Mda5 by alternative mechanisms, including NS2 from Influenza virus and V proteins of paramyxoviruses.

Host Range Tissue Ttopism and Virus Propagation

Most coronaviruses cause epidemic disease in only one species, although limited replication, usually without disease, may result from experimental inoculation of other species. Coronaviruses typically cause respiratory or enteric diseases, although several can also cause hepatitis, infectious peritonitis, nephritis, myocarditis, sialodacryadenitis, or neurological, reproductive or immunological disorders. The viruses were named for their natural host and sometimes for the associated disease for example, avian infectious bronchitis virus (IBV) mouse hepatitis virus (MHV) sialodacryadenitis virus of rats (SDAV) bovine coronavirus (BCoV) porcine hemag-glutinating encephalomyelitis virus (HEV) turkey bluecomb coronavirus (TCoV) human respiratory coronaviruses (HCoV) transmissible gastroenteritis virus of swine (TGEV) porcine respiratory coronavirus (PRCV) canine coronavirus (CCoV) feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FeCoV) and rabbit coronavirus...

Activation of Ignorant Autoreactive T Cells The Transition from Autoreactive to Autoaggressive

Historically, molecular mimicry was the first, and over a long period of time the most attractive concept of organ-specific autoimmune disease. In 1985, Fujinami and Oldstone identified a viral peptide sequence (from the hepatitis B virus polymerase) that shares sequence identity of six contiguous amino

Dermatologic Physical Exam

The strong association of LP with chronic liver disease and hepatitis in some European series has led some authors to recommend routine screening. This association has not been confirmed in North America, and at present it would seem prudent to coordinate additional testing with information revealed in the review from the general history.

Examination of the newborn infant

The examiner should be prepared to answer maternal questions and discuss the merits of BCG and hepatitis B vaccination, and routine screening tests if appropriate. Universal newborn hearing screening has recently been introduced in the United Kingdom. Universal biochemical screening for phenylketonuria and hypothyroidism during the newborn period is well established. In addition, galactosaemia, cystic fibrosis, haemoglobinopathies and various aminoacidopathies are screened for in some parts of the United Kingdom.

Clinical Features of Infection

Congenital CMV disease typically follows a subclinical primary infection of an expectant mother. Disease is much less likely to follow reactivated maternal infection, although virus transmission occurs. Perinatal infection can result in a similar disease pattern, but at a much lower frequency. While 0.5-1 of infants are infected in utero, fewer than 10 suffer disease. Cytomegalic inclusion disease is the worst manifestation of congenital CMV, representing an extremely broad spectrum of different syndromes, including petechia, hepatosplenomegaly, jaundice, microencephaly and other serious neurological damage. A majority of symptomatic infants suffer subclinical disease with slowly developing hearing loss and mental retardation. Cytomegalic inclusion disease is the most significant disease caused by CMV, and seems to be a manifestation of widespread viral growth before the immune system has had a chance to develop. Congenitally infected neonates may present with rashes, hepatitis,...

Dl Particles in Natural Infections

Nevertheless, association of a chicken influenza virus strain, efficiently producing DI particles, with an epidemic of low morbidity and low mortality, and conversely, a high-mortality epidemic associated with a strain free of DI particles, have been reported. Murine and feline leukemia virus strains causing immunedeficiency syndromes are shown to contain predominantly replication-defective viral genomes before onset and during the development of the disease. The pathogenicity of some bovine and swine pestiviruses has clearly been associated with presence of DI RNAs in the animals. For the bovine viral diarrhea virus (BVDV), a pestivirus of the same family as hepatitis C virus, the presence of a particular DI RNA can turn noncytopathic virus into a fatal infectious agent. In plants, at least three examples of DI RNAs are described to be involved in infection modulation. Interestingly, depending on the types of viruses, DI RNAs can either attenuate or exacerbate the symptoms. DI RNAs...

Pathology and Histopathology

Fulminant hepatitis presents with hypotension, profuse hemorrhage and multiple organ failure the major pathologic findings for infants dying of hepatitis are massive hepatic necrosis and extensive hemorrhage into the cerebral ventricles, renal medullae and interstitial spaces of solid organs. Inflammation is commonly found in the liver and adrenal glands.

Future Perspectives

See also Bovine diarrhea virus and Border disease virus (Flaviviridae) Chikungunya, O'nyong nyong and Mayaro viruses (Togaviridae) Dengue viruses (Flaviviridae) Encephalitis viruses (Flaviviridae) Tick-borne encephalitis and Wesselsbron viruses Equine encephalitis viruses (Togaviridae) Hepatitis C virus (Flaviviridae) Hog cholera virus (Flaviviridae) Japanese encephalitis virus (Flaviviridae) Rubella virus (Togaviridae) Sindbis and Semliki Forest viruses (Togaviridae).

Personal hygiene practices of consumers

Personal hygiene includes cleanliness of the hands, hair, clothing, and body in general. Hand washing is most frequently the sentinel behavior for assessment of personal hygiene in consumer food safety studies. From a Hazard Analysis and Critical Control Point (HACCP) perspective, the critical control point for ensuring the safety of foods that are prepared to be served without heating is personal hygiene. Controlling the transfer of pathogens from the hands to food is important for almost all foodborne illnesses, but especially (1) raw vegetables and fruits (2) some types of desserts (3) raw or undercooked foods exposed to polluted water and (4) previously cooked foods handled by consumers and served without additional heating. It is estimated that 5 of Hepatitis A cases are foodborne, 20 of Shigella cases, and 40 of Norovirus cases are estimated as being foodborne (Mead et al., 1999). Thus, hands contaminated with fecal pathogens can be the source of pathogens in foods (Feachem,...

Reverse Transcription and the Human Genome

When reverse transcriptase was first described, it was believed to be a peculiarity of retroviruses. However, researchers now know that reverse transcription also occurs during the replication of the DNA virus hepatitis B, and that RNA-copying DNA polymerases function within human cells. One of these host reverse transcriptases is telomerase, an enzyme that helps maintain chromosome ends.

Geographic and Seasonal Distribution

Many animal enteroviruses occur worldwide and may be endemic where host populations are sufficient to sustain them. However, the virulent serotype 1 PEV strain, Teschen disease virus, appears to be geographically restricted to parts of Africa and Eastern Europe, whereas the less virulent serotype 1 strains have a global distribution. Swine vesicular disease was first observed in Italy in 1966, since when outbreaks have been reported in most European countries and in Malta, Hong Kong and Japan. The continents of Africa, America and Australia have remained free of the disease. Most outbreaks have occurred in Great Britain, where they have been reported to peak in December and January. Avian encephalomyelitis was first identified in New England in 1932 and the disease has since been confirmed in many countries of the world. Duck virus hepatitis was initially reported in the USA in 1945 and then again in 1949. Since then the disease has spread to many countries in Europe, Asia, North...

Structure and Function

Some RNA viruses, such as the hepatitis delta virus, also include a ribozyme as part of their inherited RNA molecule. During replication of the viral RNA, long strands containing repeats of the RNA genome (viral genetic information) are synthesized. The ribozyme then cleaves the long multimeric molecules into pieces that contain one genome copy, and fits that RNA piece into a virus particle.

Patents and the Rise of Biotechnology Companies

Among the new companies to take advantage of the court ruling was the Chiron corporation, which cloned the protein that formed the outer coat of the human hepatitis B virus. This protein, which could now be produced without the virus that it normally enclosed, provided the material for the development of the first human vaccine using recombinant DNA technology. The hepatitis vaccine has been available since 1987.

Prevention and Control

HBV infections are prevented by measures that interrupt routes of transmission. Recognizing and identifying HBV-infected individuals permits avoidance of contacts which may lead to transmission. Changes in behavior with respect to sexual contacts and illicit intravenous drug use can reduce spread of HBV. Elimination of infected blood and plasma donors by HBsAg screening has largely eliminated HBV infections by blood transfusion and by other blood products. Screening all pregnant women for HBsAg permits protection of newborns of infected mothers by use of hepatitis B immune globulin and HBV vaccination (such passive-active immunization protects up to 95 of newborns of HBV-infected mothers).

Hare Fibroma Virus see Poxviruses

Nassal M (1996) Hepatitis B virus morphogenesis. Curr. Top. Microbiol. Immunol. 214 297. Seeger C and Mason WS (1996) Replication of the hepatitis virus genome. In dePamphilis E (ed.) DNA Replication in Eukaryotic Cells, p. 815. Cold Spring Harbor Cold Spring Harbor Laboratory Press. Avian Hepatitis B Virus

Properties of the Proteins

Hepadnaviruses produce a large excess of the envelope proteins, above the amount needed for virion assembly, and the excess is secreted as surface antigen particles. The S protein appears to be sufficient for production of surface antigen by orthohepadnaviruses, though L can also be incorporated into these particles. Both L and S have been detected in surface antigen particles produced by duck hepatitis B virus, the prototype avihepadnavirus. The surface antigen particles produced by avihepadna-viruses are pleomorphic spheres, 40-60 nm in diameter, whereas orthohepadnaviruses produce regular, 22 nm diameter rods and spheres. The particles produced by the orthohepadnaviruses may have a much lower lipid content than those produced by the avihepadnaviruses, and in neither case has the mechanism of assembly been determined, although, as for the virions, the particles first appear in the cisternae of the endoplasmic reticulum. Figure 2 The replication of duck hepatitis B virus within...

Host Range and Virus Propagation

Duck hepatitis B virus infects wild mallards and related domestic ducks (Anas platyrhynchos). Transmission to the Muscovy duck and the chicken has not been successful, but the virus can be transmitted to domestic Embden and Toulouse geese and has also been detected as an apparently natural infection in domestic geese. The distribution of duck hepatitis B virus in geese and other waterfowl has not been studied in detail. The virus is not known to be infectious to mammals. The virus will infect and replicate in primary duck hepatocyte cultures, and can be transmitted to developing duck embryos. In vivo, hepatocytes produce infectious virus, which is released into the bloodstream, producing a persistent viremia in the chronic carrier. The apparently limited host range of duck hepatitis B virus is probably due to a lack of cell surface receptors for the virus in nonsusceptible species. Indeed, the virus will replicate efficiently in a chicken hepatocellular carcinoma cell line transfected...

Serologic Relationships and Variability

There are currently no defined subtypes or serotypes of duck hepatitis B virus, though there are monoclonal antibodies which distinguish between different amino acid sequences of the surface antigen. The amount of variation in nucleotide sequence in the published sequences of duck hepatitis B virus (1.2 11.6 ) appears to resemble that of hepatitis B virus subtypes (8 10 ). Sequences from three genomes cloned from ducks from the USA and Germany appear more closely related to each other (1.2-5.9 variation) than to five sequences cloned from ducks Five sequences of heron hepatitis B virus have been published. Up to 7 sequence diversity has been found in the heron hepatitis B virus isolates. The prototype heron hepatitis B virus sequence differs from duck hepatitis B virus sequences by 21.6 , somewhat more than the 16.4 variation between the woodchuck and ground squirrel hepatitis viruses.

Pathogenicity and Clinical Features of Infection

Studies of pathogenicity in the infected duck have generally focused on the liver as the main target of infection. From this limited point of view, congenital infection is apathogenic. Therefore, infection with wild-type virus does not kill host cells in the absence of an immune response. Experimental infections of birds less than 1 week of age usually produces a chronic infection, with a mild to severe, transient, hepatitis. Infection of older ducks, in contrast, almost always produces a transient infection, followed by recovery and the development of a humoral immune response to the virus envelope, with only a mild hepatitis. Infection has not been associated with a significant rise in liver enzymes in the bloodstream, or with any other clinical features, again suggesting that hepatocellular destruction is mild. It is not known if horizontal infection accelerates the development of secondary amyloidosis of the liver in ducks, a common condition in waterfowl which is seen in infected...

Pathology and Histobiology

Laboratory infection of ducklings or older birds can produce a variable degree of hepatic injury, usually mild, including portal hepatitis with penetration of the limiting plate by mononuclear lymphoid cells and, occasionally, lobular hepatitis. Portal hepatitis, by itself, is quite common in domestic ducks, irrespective of exposure to duck hepatitis B virus, whereas a periportal or lobular hepatitis can be correlated with experimental viral infection. Piecemeal and focal necrosis have also been observed, as have occasional apoptotic (eosinophilic) bodies. Chronic persistent and chronic active hepatitis have not so far been observed as a response to infection in a controlled setting. Histopathologic features have not been described that distinguish transient from chronic infection resulting from experimental inoculation of duck hepatitis B virus. The deficiency in insulin secretion reported in congenitally infected ducks is not due to an overt pancreatitis and is more probably a...

Properties of the Virion

The virion or 'Dane particle' of human hepatitis B virus (HBV) appears as a spherical structure with a diameter of approximately 42-47 nm. Within the sphere is an electron-dense core with an estimated diameter of 22 25 nm. The viral envelope consists of a lipid bilayer containing three polypeptides, termed large (L), middle (M) and small (S) surface protein (also known as pre-Sl, pre-S2 and HBsAg). Incubation of the virion with nonionic detergent releases the nucleocapsid (core particle), which contains the 3.2 kb-long, partially double-stranded viral DNA genome and the viral DNA polymerase, a reverse transcriptase. The nucleocapsid is composed of 240 monomers of core protein (core antigen, HBcAg) arranged to form an icosahedral structure with a triangulation number T 4. Dane particles and subviral core particles present in infected hepatocytes exhibit DNA polymerase (endogenous polymerase) and protein kinase activities. Although the former can add nucleotides to the 3' ends of the...

Properties of the Viral Proteins

The four protein-coding regions of the mammalian hepadnaviruses are translated into seven known proteins (Fig. 1). The core ORF codes for the 21 kDa viral capsid protein, also called hepatitis B core antigen (HBcAg) and the 16-18 kDa precore polypeptide, termed hepatitis B e-antigen (HBeAg). The HBcAg is the most highly conserved polypeptide among the mammalian hepadnaviruses showing 68 amino acid homology between HBV and GSHV (GSHcAg) and 92 between GSHV and WHV (WHcAg). It is a cytoplasmic and nuclear phospho-protein with a basic C-terminus that is essential for the packaging of viral RNA. Core polypeptide monomers form dimers that assemble into spherical shells with icosahedral symmetry consisting of 120 dimer subunits. The formation of these dimers is mediated by two long alpha helices that form spikes on the surface of nucleocapsids. Dimers are further stabilized through the formation of two homologous intermolecular disulfide bridges.

Properties of the Genome

All members of the Hepadnaviridae family have a partially double-stranded DNA genome of about 3 kb that is held in a circular conformation by a short cohesive overlap between the 5' ends of the two DNA strands (Fig. 1). One strand is always complete in virus particles, whereas the second strand is incomplete, with a 3' end that is heterogeneous in location. The incomplete strand is of plus polarity and the complete strand of negative polarity. When these viruses infect a cell, the plus strand is completed and the fully double-stranded DNA is then converted to a covalently-closed circular (CCC) molecule, which serves as a template for viral RNA synthesis (Fig. 2). The two genera of hepadnaviruses are thought to differ in that orthohepadnaviruses encode four open reading frames (ORFs) whereas the prototypic avihepadnavirus, duck hepatitis B virus, encodes only three, lacking the X ORF. This ORF appears to encode a protein that modulates transcription, possibly by acting on signal...

Serologic Relationships and Antigenic Variability

Human HAV isolates show no evidence of antigenic variability, and share no antigenic determinants with any of the other picornaviruses or human hepatitis agents. In keeping with the lack of antigenic variability among human HAV strains, the amino acid sequences of the capsid proteins are highly conserved. Indeed, intense conservation of the immunodominant antigenic sites of human HAV appears to be an important biologic characteristic of this virus. One RR CPE+ variant acquired a spontaneous neutralization escape mutation in residue 70 of 1C during persistent passage in cell culture, but this mutation was rapidly selected against on cell-free passage of the virus. However, simian HAV isolates differ significantly from human HAV at epitopes that are immunodominant in the human strains, even though the simian viruses are recognized by polyclonal human antibody to HAV. These simian viruses appear similar to neutralization escape mutants which have been recovered from human virus passaged...

Properties of the Virion and Genome Properties of the virion

The genome of HCV is single-stranded linear RNA of positive sense. It is unsegmented and consists of a 5' untranslated region of approximately 340 nucleotides (nt) that contains an internal ribosomal entry site (IRES) and several small, presumably untranslated, open reading frames (ORFs) a protein-encoding region (ORF) of approximately 9400 nucleotides, which encodes a large polyprotein precursor of approximately 3000 amino acids and a 3' untranslated region that is surprisingly complex and contains a variable region (approximately 50 nt), a poly-pyrimidine region of approximately 100 nt but variable in length and a highly conserved terminal region of approximately 100 nt that is predicted to have a complex secondary structure.

Physical Properties

Hepatitis C virus has been recovered from cesium chloride fractions with a mean density of 1.24 g cm-3. The isopycnic density of infectious HCV in sucrose has been measured at 1.06 g cm3 in serum of acutely infected patients and at 1.12gem-3 for virus recovered from cell culture. The lower density of HCV recovered from serum results from the physical association of very low density lipoprotein with virions. Virus recovered from the serum of chronically infected patients generally has a density in sucrose of 1.15-1.18 g cm-3, probably resulting from the formation of antigen-antibody complexes. The nucleocapsid of HCV was found to have a buoyant density in sucrose of 1.25gem-3. The isopycnic density of HCV in potassium bromide is 1.12gem-3. The s2ow is > 150. The virus is stable in buffer at pH 8.0-8.7 but inactivated by exposure to lipid solvents or detergents, evidence that the virus envelope contains essential lipids. It is inactivated in aqueous solution by heat at 60 C for 10 h...

Pathology and Histopatholgy

The histologic changes in acute and chronic hepatitis C cannot generally be differentiated from those occurring in other types of viral hepatitis. The histologic changes in the liver during acute viral hepatitis are hepatic inflammation and hepatocellular necrosis. Inflammatory cells, principally lymphocytes and macrophages, are present in both the parenchyma and portal areas. Swelling and eosinophilic necrosis of hepatocytes are common. Chronic hepatitis C is characterized by inflammation (lymphocytes, macrophages and histiocytes) that is largely portal in distribution and hepatocellular necrosis that is typically periportal.

Geographic Distribution

Hepatitis delta virus infection is found worldwide and is endemic in certain areas, particularly southern Italy and the Mediterranean countries. Its distribution closely parallels that of HBV infections. However, its prevalence rate does not always match that of HBV infection in different geographical areas for example, in some HBV-prevalent areas such as China, HDV infection is disproportionately low. In developed countries such as the USA, the rate of HDV infections is low in the general population and highest among intravenous drug abusers and hemophiliacs who receive blood products. Genotype I HDV has been isolated in every geographical region in the world. Genotype II so far has been found largely within Asia, primarily Taiwan and Japan. Genotype III, which is associated mostly with fulminant hepatitis, has been detected only in South America.

Prevention and Control of Infection

Because HDV infection is dependent on a concomitant HBV infection, control of HDV infection is best achieved by HBV vaccination. However, there is no effective measure to prevent HDV infection of chronic HBV carriers. No routine blood screening for HDV is currently performed however, HDV infection by contaminated blood sources can be prevented by screening for HBV. Currently, there is no specific treatment for delta hepatitis. Interferon a has been tried therapeutically with only marginal and transient effects. Ribavirin has been shown to inhibit HDV RNA replication in tissue culture.

Physiochemical Properties of the Virion

Table 1 summarizes what is known to date about the major etiologic agent of hepatitis E. The virus appears to be extremely labile and will not tolerate exposure to high concentrations of salt, including cesium chloride. Pelleting of the virus from stool suspensions or gradient fractions frequently results in loss of virus. Rate-zonal banding of 32-34 nm virus-like particles (VLPs) in linear, preformed sucrose gradients, however, was found to yield partially purified virus suitable for further immune electron microscopy (IEM) studies. The computed sedimentation coefficient for HEV was approximately 183 S, in contrast to 157 S for that of HAV, a member of the Picorna- viridae. Virus particles were sometimes found to sediment at 165 S these particles are presumed to be defective and probably lack a complete viral genome. Isopycnic banding of an aliquot of the Telixtac no. 14 stool (HEV isolate from a 1986 outbreak in southern Mexico) suspension in a potassium tartrate glycerol gradient...

Molecular Biology of Genome Structure

Epitope mapping using a strategy of overlapping peptides revealed the presence of several potential immunogenic peptides, especially in the polymerase region. However, none has been shown to be of use in diagnostic assays. ORF 2 occupies the 3'-most 2 kb of viral genomic sequence and codes for the single capsid protein of HEV. A hydrophilic electropositive region rich in arginine residues found near the N-terminus of the capsid protein serves to neutralize and encapsulate the electronegatively-charged genomic RNA. A major immunogenic epitope is located at the C-terminus of the capsid protein, and has been found to be most useful in the diagnosis of hepatitis E (see below). The small ORF 3 also codes for an immunogenic protein of 123 amino acids however, its biological role in the life cycle of the virus remains unclear.

The Internal Ribosome Entry Site IRES

The classic assay for IRES elements is the construction and analysis of dicistronic mRNAs in which the putative IRES element is introduced between two reporter sequences (see Belsham and Sonenberg 1996, 2000 Belsham and Jackson 2000). IRES elements have been defined for seven of the nine genera of picornaviruses to date. The activity of most picornavirus IRES elements is, at least, maintained when cap-dependent protein synthesis is blocked either by the cleavage of the translation initiation factor eIF4G (see below) or by the sequestration of eIF4E (the cap-binding protein) with 4E-BP1 (Pause et al. 1994a Roberts et al. 1998). However, this is not true for the hepatitis A virus (HAV) IRES (Borman and Kean 1997 Ali et al. 2001) this IRES requires the intact eIF4F complex (comprising eIF4E, eIF4A and eIF4G). No viral coding sequences or viral proteins are required for the activity of picornavirus IRES elements.

New Enterovirus types

Hepatitis A virus was provisionally classified as enterovirus 72. After decades of investigation, this virus, which inhabits the enteric tract, had been shown clearly to have many of the physicochemical properties of an enterovirus. However, it has been found to have a genetic composition sufficiently distinct to warrant its being classified as the prototype of a separate picornavirus genus. The name, hepar-navirus, has been suggested, to indicate tropism for hepatocytes and an RNA genome.

Host Range and Viral Propagation

The pig is the sole natural host of HCV. Experimental hosts include goats, sheep, calves, deer and rabbits. Although HCV can replicate in nonporcine cells, porcine kidney or testicle cells, be it primary cells or established cell lines, are normally used for propagation. Under single growth-cycle conditions, the first progeny virus is detected at 5 7h after infection, followed by an exponential growth that peaks about 15 h after infection, with yields not exceeding 50 infectious particles per cell. The major portion of infectious virus remains cell associated. The virus replicates in the cytoplasm and induces no or minimal The growth of Newcastle disease virus is enhanced in porcine testis cells infected with HCV.

Serological Relationships and Variability

Although there is antigenic variation among HCV strains, they belong to one antigenic group, as shown by extensive crossneutralization with polyclonal antisera. The antigenic variation appears to reside on the antigenic unit on the N-terminal half of E2, as well as on El. Within strains, with the use of monoclonal antibodies directed against E2, antigenic heterogeneity is observed as well. There is a clear-cut distinction between HCV and BVDV, but these viruses are antigenically closely related, as shown by various serological techniques, including immunodiffusion and neutralizing antibody tests. In addition, there is a certain degree of cross-protection, i.e. pigs given a BVDV strain can be protected against mortality, but not disease, due to HCV. The common antigens among pestiviruses reside largely on the nonstructural protein NS2.3.

Transmission and Tissue TVopism

Pigs are infected via the oronasal route. The tonsil is the primary target tissue for virus replication. The spread of high-virulent HCV through the pig is characterized by lymphatic, viremic and visceral phases. The virus primarily replicates in epithelial cells of tonsillar crypts and then invades the underlying lymphoreticular tissues. Through the lymphatic capillaries the virus is carried to lymph nodes and, after replication in these nodes, it enters the efferent blood capillaries, giving rise to a high-titered viremia. It subsequently replicates to high titers in secondary target organs, e.g. spleen, visceral lymph nodes, lymphoid structures lining the intestine and in bone marrow. It is presumably late in the viremic phase, which persists till death, that HCV invades the parenchymatous organs. Generally, the virus titers are higher in lymphoid tissues than in parenchymatous organs. The virus has an affinity for vascular

Pathogenicity and Virulence

Although there is a continuous spectrum of virulence of HCV strains, one can distinguish strains of high, intermediate and low virulence, whereas the HCV vaccines are avirulent. It is not known which viral genes are involved in the expression of virulence. The severity and outcome of infection is the result of the composite interaction of viral virulence and host factors, such as breed, age, nutritional condition and immune competence. An association may exist between virulence and antigenicity strains that are antigenically more related to BVDV seem to be less virulent. Low-virulent strains may grow optimally at 33-34 C, whereas virulent strains do so at about 39-40 C. The growth of virus in porcine alveolar macrophage cultures has been used as a marker for virulence. Virulent virus may grow to higher titers in vivo and in vitro than low-virulent strains. Whereas virulent virus thoroughly infects epithelial cells, reticular cells and macrophages in the tonsil, growth of virus of...

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).

Primary Nursing Diagnosis

Replacement therapy and drug therapy may be used prophylactically or to control mild or major bleeding episodes. Desmopressin will raise factor VIII levels two- to threefold. Factor VIII replacement therapy is indicated for active bleeding or preparation for multiple tooth extractions or major surgery. Cryoprecipitate contains high levels of factor VIII and fibrinogen. Purified plasma-derived factor VIII concentrates are derived from large pools of plasma donors. Recent methods of screening and heating of these concentrates have greatly diminished the risk of contamination with the human immunodeficiency virus (HIV) but have little effect on the risk of hepatitis transmission. High-potency factor VIII preparations (those that are highly purified) are considered to be virtually virus-free. Recombinant factor VIII contains less risk of viral transmission but has a relatively high cost. A rule of thumb is that for every 1 unit kg infused, factor VIII levels will increase 2 . In an...

Nature of Immune Responses

In nonimmunized hosts, there is a lag period after infection of at least some days (and sometimes considerably longer, e.g. human immunodeficiency virus, HIV) before components of the adaptive response are detected. It is especially during this period that nonadaptive responses are important for limiting viral responses. In humans and ferrets, a mild influenza virus infection may be limited to the upper respiratory tract, where the mucus contains substances that can inhibit influenza virus infectivity. Infection induces an inflammatory response in which a variety of cells, including monocytes and polymorphonuclear leukocytes, are extruded on to the site of infection. There is a correlation between the extent of fever caused by pyrogens such as interleukin 1 (IL-1) and the rate of decline of viral titer. Activation of natural killer (NK) cells by interferons (IFN-a and IFN- ) results in lower viral titers. Mice bearing the Mx gene are resistant to influenza virus infection due to...

Evading the Immune Response

Antigenic variation Many DNA viruses occur in antigenically different forms, known as serotypes. The number varies from a few (e.g. hepatitis B) to many (e.g. adenoviruses, > 40). Each serotype is antigenically stable, and the distribution may vary in different localities. Prior infection with one serotype often does not protect against infection by a different serotype. Owing to the lack of corrective mechanisms for RNA synthesis, RNA viruses sometimes show greater antigenic variation. Mutations leading to changes in the sequence of nucleic acid bases and hence of amino acids, which may occur during viral replication, may persist. This is called antigenic drift and the classical examples are influenza (orthomyxovirus) and HIV (retrovirus). There are also said to be more than 100 serotypes of rhinovirus (an RNA virus) but it seems possible that some are mutants which emerged because of immune pressure. It is not clear why some RNA viruses (e.g. measles,

Management Of Hbvinfected Patients

No molecular biology-based assays are necessary for the diagnosis of acute hepatitis B, which is based on serological testing. Chronic hepatitis B is defined by HBsAg persistence in serum for more than 6 months. In this setting, HBV DNA detection-quantification is necessary to determine whether or not HBV is replicating. In the presence of HBeAg, the diagnosis of replicating chronic hepatitis B can be made whatever the viral load. Chronic hepatitis due to precore HBV mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B with generally lower replication levels than HBeAg-positive patients. HBeAg-negative chronic hepatitis B (CHB) represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with mutations in the precore region of the HBV C gene inducing a stop codon that inhibits the production of HBeAg. 11 The diagnosis of HBeAg-negative CHB is based on HBsAg...

Estimation Of Infectivity

Another important reason for HBV viral load determination is the assessment of the infectivity of hepatitis B carriers. Without intervention, more than 90 of HBeAg-positive female chronic HBV carriers transmit the virus to their infants 17 of these, 85-90 develop chronic HBV infection in most cases asymptomatic themselves, thus perpetuating the infection in high-endemicity settings. Immediate postpartum immunization of the infant can efficiently prevent transmission. It has to be considered that the level of viremia present in maternal serum can only be approximated with the HBeAg assay. Recent quantitative evaluation of sera for HBV DNA using molecular hybridization technology has shown that wide fluctuations in the concentration of virus exist in HBeAg-positive carriers. Vertical transmission is rarely documented with maternal HBV DNA levels below 107 geq mL (5 pg mL). 18,19 In a recent study, no cases of trans-placental transmission of HBV were observed with maternal HBV DNA levels...

Cytokine Gene Polymorphism Candidate Genes 21 Tumor Necrosis Factor

The main interest has been focused on the genomic variations of the TNF locus Biallelic polymorphisms defined by restriction enzymes (NcoI, AspHI) or other single base-changes (-308, -238) as well as multiallelic microsatellites (TNFa-e) have been investigated in experimental in vitro studies and also in various diseases in which TNF is considered as an important or possible pathogen. Functional importance for regulation of the TNF gene has been suggested for two polymorphisms within the TNF promoter region. Single-base changes have been detected at positions -850, -376, -308, and -238 (10-13). A G to A transition at position -308 has been associated with susceptibility to cerebral malaria (14). These results could not be confirmed by another malaria study that showed fewer fever episodes in heterozygous carriers of the allele TNF2 (15). In contrast, more recent findings link altered OCT-1 binding in the TNF promoter with susceptibility to severe malaria (11). Further evidence for the...

Clinical Use against Infections

In spite of their discovery as antiviral agents, the major impetus to develop IFNs as products of biotechnology and move them into the clinics came from their antitumor activity. The first therapeutic use of IFN by physicians was sanctioned by the Food and Drug Administration, based on its effectiveness against hairy cell leukemia, probably of viral origin (HTLV-II). Approval soon followed for the clinical use of IFN against hepatitis B virus (HBV, Hepadna-viridae), where IFN is the therapeutic agent of choice. With over 200 million carriers of HBV in the world, and the strong causal relationship between HBV infection and hepatocellular carcinoma, IFN could have a formidable impact on a serious virus-mediated disease leading to malignancy. IFN-a also emerges as the only available treatment for hepatitis C virus (Flaviviridae).

Summary and Future Perspectives

Increasingly, the general medical significance of latent viral infections is being recognized. For example, latent viral infections are fundamental to the natural history of such major syndromes as AIDS and viral hepatitis. Adequate control of these and other diseases in which latent infections play significant roles can be intelligently planned and achieved when a more precise basic understanding of the latent infection is obtained.

Methods of induction of labour with a favourable cervix [6

Urgency of the labour induction, oxytocin infusion may be started with the amniotomy or may be used only if progress after amniotomy is inadequate. Because of the considerable variability in sensitivity of the myometrium to oxytocin, oxytocin is administered as a variable dose infusion, titrated against uterine contractions. A typical dosage schedule would be 1 mU min, doubling the rate of infusion every 20-30 min until adequate uterine contractions are achieved or a rate of 32 mU min is reached. Once labour is established the infusion rate may be progressively reduced, as the myometrial sensitivity increases, to a rate of about 7 mU min. Amniotomy should be avoided if the woman is not known to be free of infections such as HIV and hepatitis, in which case oxytocin infusion may be used with intact membranes.

Clinical Description of Infection

HHV-6B is the principle cause of the exanthem roseola infantum (exanthem subitum), an illness characterized by high fever and development of a rash after fever resolves. 8 HHV-7 can also cause roseola. However, the majority of children with HHV-6B or HHV-7 infection develop an undifferentiated fever, but this may be complicated in some by febrile convulsions, encephalopathy, and hepatitis. Primary infection is rare in adults but can occur including an infectious mononucleosis-type illness. Interactions between HIV-1 and HHV-6A, HHV-6B, or HHV-7 replication occur. Each of the herpesviruses can up-regulate or down-regulate HIV-1 replication under specific conditions, but the significance is uncertain. HHV-6 infection in the first year of life has been associated with more rapid HIV-1 disease progression in vertically infected infants. HHV-6A may contribute to the switch between CCR5 (M-tropic) and CXCR4 (T-tropic) virus late in HIV-1 infection. Reactivation of HHV-6A, HHV-6B, or HHV-7...

Suppression of Abnormally Activated Proinflammatory Signaling Pathways

The generation of ROS, tissue injury, or infection can create a state of inflammation, which is causally linked to tumorigenesis. Accumulating evidence suggests that chronic inflammation acts as a predispoding factor for cancers of different organs and tissues including stomach, colon, breast, skin, prostate, and pancreas 36-39 . Examples of inflammation-associated malignancies are the development of carcinomas of stomach, liver, gallbladder, prostate, and pancreas from Helicobacter pylori-induced gastric inflammation, chronic hepatitis, cholecystitis, inflammatory atrophy of the prostate, and chronic pancreatitis, respectively 40,41 . Proinflammatory mediators, such as cytokines, chemokines, prostaglandins (PGs), nitric oxide (NO), and leukotrienes, promote neoplastic transformation of cells by altering normal cellular signaling cascades 42 . For example, IL-6 and TNF-a, two proinflammatory cytokines, have been implicated in tumor promotion 43 . Moreover, the incidence and the...

Ectromelia Virus History

In 1946 Burnet, in Melbourne, showed that ectromelia virus was serologically related to vaccinia virus. During experimental epidemics carried out in Burnet's laboratory, Fenner found that in animals that did not die of acute hepatitis there was a rash, and he named the disease mousepox. Subsequent studies led to the development of a model to explain the spread of virus around the body in generalized virus infections with rash.

Other Keratin Disorders

Recent studies have revealed that mutations in keratins expressed in simple epithelia may be involved in the pathogenesis of a number of gastrointestinal diseases. 20 Cryptogenic cirrhosis is a diagnosis of exclusion applicable to an individual with cirrhosis who does not carry a hepatitis B or C virus who does not test positive for serological markers associated with autoimmune hepatitis or primary biliary cirrhosis who has normal iron, ceruloplasmin, and aj-antitrypsin levels and who has no history of alcohol or toxin ingestion. Recurrent mutations in human K8 K18 genes have been shown to predispose individuals to cryptogenic cirrhosis, chronic pancreatitis, and inflammatory bowel disease. 20,34,35 How K8 K18 mutations cause liver disease is still a matter of debate. Animals deficient in K8 K18 are highly susceptible to proapoptotic signals, suggesting that keratins may play a cytoprotective role in the gastrointestinal tract. 20

Findings In Other Cytokine Candidate Genes

In viral infections, IL10-1082 promoter polymorphism has been associated with susceptibility to chronic hepatitis C infection and resistance to antiviral therapy (50). Another publication suggests that high IL-10 secretion indicated by the -1082 polymorphism or the promoter haplotype defined by single nucleotide polymorphisms at positions -1082, -819, and -592 protects against Epstein-Barr virus infection (51,52).

Potential for a cytoplasmic disulfide bond

Perhaps the most surprising observation from model building and refinement of the structure was the presence of a disulfide bond near the C-terminus of domain I. The disulfide bond connects the sidechains of the conserved Cys 142 and Cys 190, resulting in a covalent link between the loop exiting from p-strand B6 to the C-terminal extension of strand B9 (Fig. 3A). Model refinement without a disulfide at this position placed the sidechains of these cysteine residues in an unfavorable proximity. Refinement with the disulfide led to no problematic geometry for either cysteine residues, and generated a model that better fit the electron density (Fig. 3A). Density corresponding to the disulfide bond is present in both molecules of domain I in the asymmetric unit, providing two independent views of this feature. The disulfide bond in the model results in a sulfur to sulfur atom distance of 2.03 A, an ideal value for bond formation.9 Analysis of the purified domain I protein in the presence...

A dimeric NS5A reveals potential molecular interaction surfaces

A surface of domain I that was of considerable interest was the buried region between monomers to create the dimeric domain I seen in the crystal structure (Fig. 4). The dimer interface of 678 A2 consists of two patches of buried surface area, one located primarily in subdomain IA, and a second located in subdomain IB. The total buried surface area in the domain I dimer is more than the generally accepted standard of 600 A2 for protein interfaces and has good shape and electrostatic complementarity.19 The contact patch in subdomain IA contains a number of conserved residues, whereas the smaller patch in subdomain IB is of lower sequence conservation. It is important to note that residues of lower conservation involved in the dimer interface appear to primarily be involved in mainchain contacts, suggesting some sequence plasticity is allowable at these positions. The zinc-binding site is close to the interface between monomers and may represent a factor involved in NS5A...

Clinical Manifestations

Hepatitis disseminated infection that can mimic some aspects of bacterial sepsis. CVB4 infection is associated with a higher risk for severe disease in infants less than 1 month old, but other CVB serotypes and other entero-viruses can also cause similarly severe disease in this age group. Neonatal disease can also include other typical enterovirus syndromes, such as meningitis, encephalitis, pneumonia, hepatitis, myocarditis, and pancreatitis. One systematic study in Nassau County, New York, estimated that one of every 2000 infants in that area was hospitalized during the first 3 months of life for CVB sepsis-like disease, with significant mortality. This probably underestimates the true rate, since virus isolation studies may be insensitive and other enteroviruses were not included in the estimate.

As Comprehensive Gene Expression Profiling

The clinical challenges mentioned above point to a need to understand in a comprehensive fashion the underlying molecular mechanisms of kidney cancers. One recent biomedical breakthrough is the use of high-throughput microarray technology, which allows comprehensive gene expression profiling of tumors. These gene expression profiles can serve as the molecular signatures of particular tumors, and they may be used to distinguish among histological subtypes and novel distinct subtypes that are correlated with clinical outcome. This distinction may reflect the heterogeneity in transformation mechanisms, cell types, or aggressiveness among tumors. For example, approx 100 genes were identified as differentially expressed by serous as compared to mucinous ovarian cancers (27). Other studies have identified distinct gene sets that distinguish between acute myeloid leukemia and acute lymphoblastic leukemias (28), between hereditary breast cancer with BRCA1 and BRCA2 mutations (29), and between...

NS2 is a cysteine protease

Catalysis of a peptide bond by cysteine proteases proceeds through a well-characterized, charge relay network mechanism. The NS2 structure suggests that Glu 163 polarizes His 143 to deprotonate the cysteine side chain. The nucleophilic Cys 184 attacks the carbonyl of the scissile bond forming a negatively charged, tetrahedral transition state. Cleavage of the activated intermediate releases the N terminus of NS3 and creates an acyl-enzyme intermediate in which Cys 184 is covalently bonded to Leu 217. Hydrolysis of the acyl-enzyme intermediate forms the carboxylic acid of Leu 217 and restores the proton to Cys 184. Interestingly, Pro 164, which is adjacent to Glu 163 of the catalytic triad, has a c s-peptide conformation with the pyrrolidine ring lying on the same side as the carbonyl group of Glu 163 (Fig. 6). This proline residue is entirely conserved in HCV and the related GB virus sequences, implying that this position has an important

Viruses Affecting the Heart

Commonly e.g. enteroviruses, human immunodeficiency virus (HIV) and, if acquired congenitally, rubella whereas others are uncommon e.g. varicel-la-zoster, cytomegalovirus (CMV) and hepatitis B . Many of these viruses involve the heart as part of a clinically obvious generalized infection (e.g. varicella, mumps and rabies) whereas in others, cardiac disease is the primary presenting clinical feature. The more common causes of viral heart disease are discussed below, but some of those occurring less commonly are listed in Table 1.

Viruses Affecting the Pancreas

Nevertheless, studies on children with disseminated fatal viral infections showed that pancreatic lesions, often with islet cell destruction, were present in patients with coxsackie B, CMV, varicella-zoster and congenitally acquired rubella. In addition, pancreatitis has been observed following mumps and, less commonly, following Epstein-Barr virus (EBV) infection and hepatitis B virus infections. The finding that hepatitis B surface and core antigens have been detected in the acinar cells of patients with hepatitis B antigenemia suggests that this virus may replicate in pancreatic tissue. Although such filoviruses as Marburg and Ebola induce generalized infections with severe hepatic involvement, some patients develop clinical features of acute pancreatitis, and postmortem studies have demonstrated areas of focal pancreatic necrosis.

Nonstructural Proteins

The sequences of 3Cpros show that they belong to the chymotrypsin-like family of serine proteases, and the high degree of conservation suggests that the three-dimensional structures for rhinovirus, hepatitis A and poliovirus (Matthews et al. 1994 Allaire et al. 1994 Mosimann et al. 1997) should provide reasonable models for other members of the family (Fig. 4). However, there is a difference in the nature of the catalytic site whereby the family divides into two lineages. The entero- and rhi-noviruses have a Glu as a member of the serine proteinase-like catalytic triad which interacts with a His, as observed in the HRV14 structure. The Asp which replaces the Glu (conserved in lineage B) was observed in the hepatitis A 3C proteinase structure not to interact with the histi-dine (Allaire et al. 1994), a water molecule fulfilling this role. Biochemical studies have identified the residues involved in the catalytic triad in FMDV 3Cpro as Cys163, His46 and Asp84 (Grubman 1995). Thus FMDV...

Evidence in favor of a NS2 dimer

A series of experiments in mammalian cells was designed to test whether NS2pro can form dimers with a functional composite active site in vivo. HCV full-length polyproteins containing either a H143A or a C184A mutation in the NS2 active site are defective in NS2-3 processing.1314 However, if a composite active site can form, co-expression of the two. mutant polyproteins should result in partial NS2-3 cleavage (see figure 3 in ref 27). Indeed, when HCV polyproteins with NS2 containing either a H143A or C184A mutation were co-expressed, NS2 and NS3 cleavage products were detected, indicating the formation of a functional composite active site. These data strongly support the NS2pro crystal structure and prove that NS2 can form dimers with composite functional active sites.

Respiratory disorders

Varicella pneumonia is a particular cause for concern for the pregnant woman requiring intravenous acyclovir. It can occur in association with encephalitis and hepatitis. Up to 10 of women affected by varicella will develop pneumonia and will require admission for intravenous treatment. There does not appear to be adverse sequelae for the fetus from acyclovir and case fatality rates have reduced to 1 or less with acyclovir treatment.

Commercial Application

Transgenic microbes have many commercial and practical applications, including the production of mammalian products. A company called Genentech was among the earliest and most successful commercial enterprises to use genetically engineered bacteria to produce human proteins. Their first product was human insulin produced by genetically engineered Escherichia coli. A variety of other human hormones, blood proteins, and immune modulators are now produced in a similar fashion, in addition to vaccines for such infectious agents as hepatitis B virus and measles.

DI Particles in Natural Infections

Nevertheless, association of a chicken influenza virus strain, efficiently producing DI particles, with an epidemic of low morbidity and low mortality, and conversely, a high-mortality epidemic associated with a strain free of DI particles, have been reported. Murine and feline leukemia virus strains causing immune deficiency syndromes are shown to contain predominantly replication-defective viral genomes before onset and during the development of the disease. The pathogenic-ity of some bovine and swine pestiviruses has clearly been associated with presence of DI RNAs in the animals. For the bovine viral diarrhea virus (BVDV), a pestivirus of the same family as hepatitis C virus, the presence of a particular DI RNA can turn noncytopathic virus into a fatal infectious agent. In plants, at least three examples of DI RNAs are described to be involved in infection modulation. Interestingly, depending on the types of viruses, DI RNAs can either attenuate or exacerbate the symptoms. DI RNAs...

Preoperative Assessment Patient Selection

All donor candidates require extensive medical and psychological evaluation in accordance with guidelines published by the American Society of Transplant Physicians (12). The transplantation team must carefully evaluate the donor's motivation and emotional stability. In addition, donor candidates must undergo a battery of laboratory studies for histocompatibility testing and to ensure that the patient will be left with normal renal function following unilateral nephrectomy. Standard blood tests include a complete blood count, serum chemistries, coagulation profile, ABO histocompatibility, and HLA crossmatching. Other serologic tests include that for hepatitis B and C, syphilis, human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella. Urine tests include a urinalysis, urine culture, and a 24-h urine collection for creatinine clearance and protein.