Virus hepatic

There are two causes for concern: failure to detect HBsAg may lead to transmission through donated blood or organs, and HBV may infect individuals who are anti-HBs positive after immunization. Variation in the second loop of the a determinant seems especially important.

Mutants, variants, altered genotypes, and unusual strains are now being sought in many laboratories. The nucleotide sequence of the genome of a strain of HBV cloned from the serum of a naturally infected chimpanzee has been reported. A surprising feature was a point mutation in the penultimate codon of the precore region which changed the tryptophan codon TGG to an amber termination codon TAG. An identical mutation of the penultimate codon of the precore region to a termination codon was found in seven of eight anti-HBe positive patients who were positive for HBV DNA in serum by hybridization.

In most cases there was an additional mutation in the proceeding codon. These variants are not confined to the Mediterranean region. The same nonsense mutation without a second mutation in the adjacent codon has been observed in patients from Japan and elsewhere, along with rarer examples of defective precore regions caused by frameshifts or loss of the initiation codon for the precore region.

In many cases, precore variants have been described in patients with severe chronic liver disease and who may have failed to respond to therapy with interferon. This observation raises the question of whether they are more pathogenic than the wild-type virus. When tests for HBsAg became widely available, regions of the world where the chronic carrier state is common were found to be coincident with those where there is a high prevalence of primary liver cancer.

Furthermore, in these areas, patients with tumor almost invariably are seropositive for HBsAg. A prospective study in Taiwan revealed that cases of hepatocellular carcinoma occurred in 3, carriers of HBsAg at the start of the study, but only 10 such tumors arose in the 19, control males who were HBsAg negative.

There is no similarity in the pattern of integration between different tumors, and variation is seen both in the integration site s and in the number of copies or partial copies of the viral genome. Integration seems to involve microdeletion of host sequences and rearrangements and deletions of part of the viral genome also may occur. When an intact surface gene is present, the tumor cells may produce and secrete HBsAg in the form of 22 nm particles. Production of HBcAg by tumors is rare, however, and the core ORF is often incomplete and modifications such as methylation may also modulate its expression.

Cytotoxic T cells targeted against core gene products on the hepatocyte surface seem to be the major mechanism of clearance of infected cells from the liver, and cells with integrated viral DNA which are capable of expressing these proteins also may be lysed.

The mechanisms of oncogenesis by HBV remain obscure. HBV may act non-specifically by stimulating active regeneration and cirrhosis which may be associated with long-term chronicity. However, HBV-associated tumors occasionally arise in the absence of cirrhosis, and such hypotheses do not explain the frequent finding of integrated viral DNA in tumors. In rare instances, the viral genome has been found to be integrated into cellular genes such as cyclin A and a retinoic acid receptor.

Translocations and other chromosomal rearrangements also have been observed. Although insertional mutagenesis of HBV remains an attractive hypothesis to explain its oncogenicity, there is insufficient supportive evidence. Like many other cancers, development of hepatocellular carcinoma is likely to be a multifactorial process. The clonal expansion of cells with integrated viral DNA seems to be an early stage in this process and such clones may accumulate in the liver throughout the period of active virus replication.

In areas where the prevalence of primary liver cancer is high, virus infection usually occurs at an early age and virus replication may be prolonged, although the peak incidence of tumor is many years after the initial infection. Delta hepatitis was first recognized following detection of a novel protein, delta antigen HDAg , by immunofluorescent staining in the nuclei of hepatocytes from patients with chronic active hepatitis B. HDV is coated with HBsAg which is needed for release from the host hepatocyte and for entry in the next round of infection.

Two forms of delta hepatitis infection are known. Vaccination against HBV also prevents co-infection. This may cause a second episode of clinical hepatitis and accelerate the course of the chronic liver disease, or cause overt disease in asymptomatic HBsAg carriers. In areas of low prevalence of HBV, those at risk of hepatitis B, particularly intravenous drug abusers, are also at risk of HDV infection.

The HDV genome is a closed circular RNA molecule of nucleotides and resembles those of the satellite viroids and virusoids of plants and similarly seems to be replicated by the host RNA polymerase II with autocatalytic cleavage and circularization of the progeny genomes via trans -esterification reactions ribosome activity.

Consensus sequences of viroids which are believed to be involved in these processes also are conserved in HDV. This is encoded in an open reading frame in the antigenomic RNA but four other open reading frames which are also present in the genome do not appear to be utilized. The antigen, which contains a nuclear localization signal, was originally detected in the nuclei of infected hepatocytes and may be detected in serum only after stripping off the outer envelope of the virus with detergent.

Transmission studies in chimpanzees established that the main agent of parenterally acquired non-A, non-B hepatitis was likely to be an enveloped virus some 30 to 60 nm in diameter. These studies made available a pool of plasma which contained a relatively high titer of the agent.

In order to clone the genome, the virus was pelleted from the plasma. The resultant cDNA was then inserted into the bacteriophage expression vector lambda gt 11 and the libraries screened using serum from a patient with chronic non-A, non-B hepatitis. This approach led to the detection of a clone designated which was found to bind to antibodies present in the sera of several individuals infected with non-A, non-B hepatitis.

This clone was used as a probe to detect a larger, overlapping clone in the same library. It was possible to demonstrate that these sequences hybridized to a positive-sense RNA molecule of around 10, nt which was present in the livers of infected chimpanzees but not in uninfected controls.

No homologous sequences could be detected in the chimpanzee or human genomes. Thus, clones covering the entire viral genome were assembled and the complete nucleotide sequence determined. Successful cloning of portions of the viral genome permitted the development of new diagnostic tests for infection by the virus. Since the original antigen was detected by antibodies in the serum of an infected patient it was an obvious candidate for the basis of an ELISA to detect anti-HCV antibodies.

A larger clone, C, was assembled from a number of overlapping clones and expressed in yeast as a fusion protein using human superoxide dismutase sequences to facilitate expression, and this fusion protein formed the basis of first generation tests for HCV infection.

The antigen comprises amino acid sequences from the non-structural, NS4, region of the genome and C contains both NS3 and NS4 sequences. It is now known that antibodies to C are detected relatively late following an acute infection. Furthermore, the first generation ELISAs were associated with a high rate of false positive reactions when applied to low incidence populations, and there were further problems with some retrospective studies on stored sera.

Data based on this test alone should, therefore, be interpreted with caution. Second generation tests include antigens from the nucleocapsid and further non-structural regions of the genome. The former C22 is particularly useful and antibodies to the HCV core protein seem to appear relatively early in infection.

These second generation tests confirm that HCV is the major cause of parenterally transmitted non-A, non-B hepatitis. Routine testing of blood donations is now in place in many countries and prevalence rates vary from 0. Most of those with antibody have a history of parenteral risk such as a history of transfusion or administration of blood products or of intravenous drug abuse.

There is little evidence for sexual or perinatal transmission of HCV and it is not clear what are the natural routes of transmission. The availability of the nucleotide sequence of HCV made possible the use of the polymerase chain reaction PCR as a direct test for the genome of the virus.

Whether the virus is cytopathic or whether there is an immunopathological element remains unclear. HCV infection is also associated with progression to primary liver cancer. For example, in Japan, where the incidence of hepatocellular carcinoma has been increasing despite a decrease in the prevalence of HBsAg, HCV is now considered the major risk factor.

There is no DNA intermediate in the replication of the HCV genome or integration of viral nucleic acid and viral pathology may contribute to oncogenesis through cirrhosis and regeneration of liver cells. HCV rarely seems to cause fulminant hepatitis. It has been proposed that HCV should be the prototype of a third genus in the family Flaviviridae. All of these genomes contain a single large open reading frame which is translated to yield a polyprotein of around amino acids in the case of HCV from which the viral proteins are derived by post-translational cleavage and other modifications.

The amino acid sequence of the nucleocapsid protein seems to be highly conserved among different isolates of HCV. The next domain in the polyprotein also has a signal sequence at its carboxyl-terminus and may be processed in a similar fashion.

These glycoproteins have not been visualized in vivo and the molecular sizes are estimated from sequence data and expression studies in vitro. Other post-translational modifications, including further proteolytic cleavages, are possible.

These proteins are the focus of considerable interest because of their potential use in tests for the direct detection of viral proteins and for HCV vaccines. Nucleotide sequencing studies reveal that both domains contain hypervariable regions. It is possible that this divergence has been driven by antibody pressure and that these regions specify important immunogenic epitopes. In the flaviviruses, NS3 has two functional domains, a protease which is involved in cleavage of the non-structural region of the polyprotein and a helicase which is presumably involved in RNA replication.

Motifs within this region of the HCV genome have homology to the appropriate consensus sequences, suggesting similar functions. Hepatitis C virus consists of a family of highly related but nevertheless distinct genotypes, numbering at present 6 genotypes and various subtypes with differing geographical distribution, and with a complex nomenclature.

The C, NS3 and NS4 domains are the most highly conserved regions of the genome, and therefore these proteins are the most suitable for use as capture antigens for broadly reactive tests for antibodies to HCV. The sequence differences observed between HCV groups suggest that virus-host interactions may be different, which could result in differences in pathogenicity and in response to antiviral therapy.

It is important, therefore, to develop group- and virus-specific tests. The degree of divergence apparent within the viral envelope proteins implies the absence of a broad cross-neutralizing antibody response to infection by viruses of different groups. Indeed, sequence changes within this region may occur during the evolution of disease in individual patients and may play an important role in progression to chronicity. Neutralizing antibodies have not been identified so far.

The virus has not been cultivated in vitro cf. Yellow fever flavivirus, which has been cultured and from which vaccines have been prepared. Nevertheless, approaches to vaccine development could be based on techniques used for the development of vaccines against the Flaviviruses and Pestiviruses. About 30 years ago, a series of transmission studies of human viral hepatitis were initiated in small South American tamarins or marmosets, which were chosen because of their very limited contact with man, implying that they were unlikely to have been infected with human viruses.

A serum which was obtained on the third day of jaundice from a young surgeon GB with jaundice-induced hepatitis in each of four inoculated marmosets and was passaged serially in these animals. These important observations remained controversial until the application recently of modern molecular virological techniques. Cross-challenge experiments showed that infection with the original infectious tamarin inoculum conferred protection from reinfection with GBV-B but not GBV-A.

The organization of the genes of the GBV-A, B, and C genomes shows that they are related to other positive-strand RNA viruses with local regions of sequence identity with various flaviviruses.

Diagnostic reagents were prepared with recombinant antigens, and limited testing was carried out in groups of patients, blood donors and other selected individuals: patients with non-A, B, C, D, E hepatitis, multitransfused patients, intravenous drug addicts and other populations with a high incidence of viral hepatitis. The development and availability of specific diagnostic reagents will establish the epidemiology of these newly identified viruses, their pathogenic significance in man and their clinical and public health importance.

Turn recording back on. National Center for Biotechnology Information , U. Show details Baron S, editor. Inflammation can damage organs. Researchers have discovered several different viruses that cause hepatitis, including hepatitis A, B, C, D, and E. People may also get hepatitis E by eating undercooked pork, deer, or shellfish.

Hepatitis B and D may also spread through contact with other body fluids. Hepatitis B spreads through contact with blood, semen or other body fluids from an infected person. Your risk of hepatitis B infection increases if you:. Having a chronic HBV infection can lead to serious complications, such as:.

The hepatitis B vaccine is typically given as three or four injections over six months. You can't get hepatitis B from the vaccine. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press.

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The hepatitis B virus can also be transmitted from: Birth to an infected mother Sex with an infected person Sharing equipment that has been contaminated with blood from an infected person, such as needles, syringes, and even medical equipment, such as glucose monitors Sharing personal items such as toothbrushes or razors Poor infection control has resulted in outbreaks in health care facilities Hepatitis C is spread when blood from a person infected with the Hepatitis C virus — even in microscopic amounts — enters the body of someone who is not infected.

The hepatitis C virus can also be transmitted from: Sharing equipment that has been contaminated with blood from an infected person, such as needles and syringes Receiving a blood transfusion or organ transplant before when widespread screening virtually eliminated hepatitis C from the blood supply Poor infection control has resulted in outbreaks in health care facilities Birth to an infected mother Who should be vaccinated?

International travelers to countries where hepatitis B is common People with hepatitis C People with chronic liver disease People with HIV People who are in jail or prison All other people seeking protection from hepatitis B virus infection There is no vaccine available for hepatitis C.

Symptoms: Many people with hepatitis do not have symptoms and do not know they are infected. Hepatitis A. Hepatitis B. Hepatitis C. Hepatitis D. Hepatitis E. Viral Hepatitis Home. Links with this icon indicate that you are leaving the CDC website. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.

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