non-A non-B Hepatitis Virus Research Articles

Unexplained diarrhoea in HIV-1 infected individuals.

BackgroundGastrointestinal symptoms, in particular diarrhoea, are common in non-treated HIV-1 infected individuals. Although various enteric pathogens have been implicated, the aetiology of diarrhoea remains unexplained in a large proportion of HIV-1 infected patients. Our aim is to identify the cause of diarrhoea for patients that remain negative in routine diagnostics.MethodsIn this study stool samples of 196 HIV-1 infected persons, including 29 persons with diarrhoea, were examined for enteropathogens and HIV-1. A search for unknown and unexpected viruses was performed using virus discovery cDNA-AFLP combined with Roche-454 sequencing (VIDISCA-454).ResultsHIV-1 RNA was detected in stool of 19 patients with diarrhoea (66%) compared to 75 patients (45%) without diarrhoea. In 19 of the 29 diarrhoea cases a known enteropathogen could be identified (66%). Next to these known causative agents, a range of recently identified viruses was identified via VIDISCA-454: cosavirus, Aichi virus, human gyrovirus, and non-A non-B hepatitis virus. Moreover, a novel virus was detected which was named immunodeficiency-associated stool virus (IASvirus). However, PCR based screening for these viruses showed that none of these novel viruses was associated with diarrhoea. Notably, among the 34% enteropathogen-negative cases, HIV-1 RNA shedding in stool was more frequently observed (80%) compared to enteropathogen-positive cases (47%), indicating that HIV-1 itself is the most likely candidate to be involved in diarrhoea.ConclusionUnexplained diarrhoea in HIV-1 infected patients is probably not caused by recently described or previously unknown pathogens, but it is more likely that HIV-1 itself plays a role in intestinal mucosal abnormalities which leads to diarrhoea.

Discovery of the hepatitis C virus

After nearly 6 years of intensive investigations between 1982 and 1988 in my laboratory at Chiron corporation, in which numerous molecular biological methods were used to investigate the viral aetiology of parenterally transmitted non-A, non-B viral hepatitis (NANBH), a single cDNA clone (5-1-1) was isolated that was shown to be derived from a new flavi-like virus, termed the hepatitis C virus (HCV). After screening hundreds of millions of bacterial cDNA clones derived from different liver and plasma samples obtained from experimentally infected chimpanzees, a single HCV clone was eventually isolated using a novel, blind immunoscreening method in which antibodies derived from a clinically diagnosed NANBH patient were used to identify a cDNA clone encoding an immunodominant epitope within HCV nonstructural protein 4. Its viral origin was demonstrated by its specific hybridization to a large single-stranded RNA molecule of approximately 10,000 nucleotides found only in NANBH-infected samples that shared distant sequence identity with flaviviruses. Further, HCV clone 5-1-1 was shown to be extrachromosomal and to encode an antigen eliciting antibody seroconversion only in NANBH-infected chimpanzees and humans. Subsequent work demonstrated that HCV was the principal cause of parenterally transmitted NANBH around the world, with an estimated 170 million global carriers and that blood screening tests detecting circulating HCV antibodies and viral RNA could effectively eradicate the transmission of transfusion-associated NANBH. Key viral-encoded enzymes essential to its life cycle are now the targets of vigorous, ongoing drug development activities, and the feasibility of successful vaccination strategies has been demonstrated using the valuable chimpanzee model, without which any progress on HCV would not have been possible. My colleagues and coworkers who made essential contributions to the discovery of HCV were George Kuo, who had his own laboratory at Chiron and who provided intellectual and practical input, Dan Bradley of the Centers for Disease Control and Prevention, who provided a large supply of well-characterized chimpanzee samples and knowledge of the NANBH field, and Qui-Lim Choo, in my own laboratory, who provided many years of outstandingly dedicated and precise molecular biology expertise.

Sexual transmission of hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) is the cause of almost all cases of parenterally transmitted non-A, non-B viral hepatitis (NANBH). HCV is an RNA virus, unrelated to the hepatitis viruses,...

Genoepidemiology and pathogenicity of hepatitis G virus in Japan.

A recently discovered non-A non-B hepatitis virus has been designated hepatitis G virus (HGV). Blood contamination has been proposed as its mode of transmission. We studied the genoprevalence of HGV in Japanese people at high risk. HGV was identified in serum by a reverse-transcription polymerase chain reaction. HGV was detected in 16.0% of intravenous drug users (IDUs) (n = 25), 16.2% of those with tattoos (n = 37), 10.9% of IDUs with tattoos (n = 55), 5.7% of chronic hepatitis (CH)-C patients (n = 87), and in none of the CH-B (n = 50) or CH non-B non-C (n = 46) patients. Serum alanine aminotransferase (ALT) levels of those infected with HGV alone (n = 3) were all within normal range. In the patients with CH-C, serum ALT levels of those coinfected with HGV were similar to serum ALT levels of those without HGV infection. A phylogenetic tree of isolated HGV clones showed that the HGVs of these subjects bore only a distant-resemblance to clones reported from Africa and North America, and that variation in the phylogenetic index of HGV clones was small. These results suggest that HGV clones from different areas have genetic heterogeneity and that HGV causes no or mild hepatitis.

Common clinical criteria do not predict spontaneous recovery in non-acetaminophen induced acute liver failure: [formula omitted]. Mount Sinai Medical Center, New York, N.Y.

Background: Although non-A, non-B (NANB) viral hepatitis has been implicated as an etiology of fulminant hepatitis, hepatitis C virus (HCV) has not been shown to result in acute hepatic failure and hepatitis E virus (HEV) has predominantly been associated with fulminant hepatitis among pregnant women. Methods: Using polymerase chain reaction to detect HCV and HEV genomes, four-antigen radioimmunoblot assay (4-RIBA) to measure anti-HCV antibodies, and enzyme-linked immunosorbent assay (ELISA) to detect anti-HEV immunoglobulin M (IgM) antibodies, 17 patients with sporadic fulminant or subfulminant hepatitis of presumed NANB viral etiology were studied. Results: The diagnosis of acute NANB viral hepatitis was made based on clinical information, serological tests, biochemical profiles, and pathological features. All 17 patients were negative for anti-HEV IgM antibodies and HEV RNA in either serum and/or liver. HCV RNAs were detected in 2 patients although anti-HCV antibodies were negative in all of them. Conclusions: It is shown that HCV is infrequently associated with and HEV is not an identifiable cause of presumed NANB fulminant or subfulminant hepatitis in this patient population. Although further studies will be required for identification of the causative agent, it is possible that another agent is responsible for the occurrence of sporadic NANB fulminant or subfulminant hepatitis.

Donor Pool May Rise as Screening Blood Test Falls

THOUSANDS OF NEW volunteer blood donors may be added to increase the dangerously low national pool as soon as blood banks are able to review and put into effect a recent recommendation from the National Institutes of Health (NIH). One screening test for hepatitis B core antigen in the blood of potential donors has outlived its usefulness and should be discontinued, a panel of experts convened by the NIH last month concluded. Use of the alanine transaminase (ALT) test (also known as alanine aminotransferase) as a tool for identifying blood that may transmit posttransfusion non-A, non-B (NANB) hepatitis began during 1986 and 1987. It was introduced by blood banks acting largely on a recommendation made in 1985 by an advisory committee of the Food and Drug Administration. Lacking a direct means of detecting NANB hepatitis virus, blood banks used the liver enzyme—measuring test as a surrogate marker for the virus's

Intrahepatic Cholangiocarcinomas Associated with Nonbiliary Cirrhosis

To determine the prevalence and clinicopathologic features of cholangiocarcinoma (CC) associated with nonbiliary cirrhosis, we performed a clinicopathologic study. Among the 5,563 autopsies in our laboratories during the past 14 years, 85 (1.5%) were CCs. Four (4.7%) were associated with cirrhosis, due to hepatitis B virus in one case and cryptogenic (probably non-A non-B hepatitis virus) in the remaining three. Clinically, patients with CC and cirrhosis were characterized by male preponderance, lower age, past history of liver injury, and elevated values of zinc sulfate and thymol turbidity tests. Pathologically, all CCs with cirrhosis were basically adenocarcinoma; other histologic features included adenocarcinoma resembling bile ductules without mucin (one case), adenocarcinoma with broad areas of signet ring cell carcinoma (one case), adenocarcinoma with extensive sarcomatoid transformation (one case), and adenocarcinoma associated with hepatoliths (one case). Immunohistochemically, immunophenotypes of carcinoma cells of CC with cirrhosis were not different from those of CC without cirrhosis. Carcinoembryonic antigens, CA19-9, DU-PAN-2, and biliary-type cytokeratins were positive and alpha-fetoprotein was negative, suggesting that our CCs are not hepatocellular neoplasms but true CCs. It must be stressed that there are actual CCs arising in nonbiliary cirrhotic livers.

A clinicopathologic study of adenomatous hyperplasia of the liver in 209 consecutive cirrhotic livers examined by autopsy.

Adenomatous hyperplasia (AH), also called macroregenerative nodule, of the cirrhotic liver is currently considered to be a preneoplastic or early neoplastic lesion in human hepatocellular carcinogenesis. The authors surveyed 209 consecutive cirrhotic livers from patients who had undergone autopsy at our laboratory during the last 18 years (1974-1991), and examined the prevalence and clinicopathologic characteristics of cirrhotic livers with AH. AH was classified into two types: ordinary and atypical. Ordinary AH (OAH) is devoid of hepatocellular atypia, whereas atypical AH (AAH) consists of atypical hepatocytes equivocal as to benignity and malignancy and occasionally contains overt malignant foci. A total of 123 AH were found in 45 (21.5%) of the 209 cirrhotic livers; 38 AAH were found in 12 cirrhotic livers (5.7%), and 85 OAH was found in 41 cirrhotic livers (19.6%). Nineteen AAH contained overt malignant hepatocellular foci. Comparing the first 9 years (1974-1982) with the latter 9 years (1983-1991), 4 (3.8%) of 104 cirrhotic livers harbored AAH in the first period, and 8 (7.4%) of 105 cirrhotic livers contained AAH in the latter period. Sixteen (15.4%) of 104 cirrhotic livers harbored OAH in the first period, and 25 (23.8%) of 105 cirrhotic livers contained OAH in the latter period. Etiology of the 12 cirrhotic livers with AAH was as follows: 1 was hepatitis B virus, 10 were non-A non-B hepatitis virus, and 1 was primary biliary cirrhosis. Etiology of 41 cirrhotic livers with OAH was as follows: 16 were hepatitis B virus, 18 were non-A non-B hepatitis virus, and 7 were other causes. AAH occurred commonly in mixed nodular cirrhosis, whereas OAH occurred usually in macronodular or mixed nodular cirrhosis. All 12 cirrhotic livers with AAH were associated with hepatocellular carcinoma (HCC), particularly HCC of nodular type, whereas 17 cirrhotic livers with OAH were associated with HCC and the remaining 24 cirrhotic livers with OAH were not associated with HCC. These results suggest that the number of cirrhotic livers with AH is increasing gradually, and that cirrhotic livers with AAH are characterized by the association with non-A non-B hepatitis virus as well as simultaneous occurrence of HCC. Thus, AAH may be an important preneoplastic lesion in cirrhotic livers associated with non-A non-B hepatitis virus (probably hepatitis C virus).

Fulminant or subfulminant non-A, non-B viral hepatitis: The role of hepatitis C and E viruses

Background: Although non-A, non-B (NANB) viral hepatitis has been implicated as an etiology of fulminant hepatitis, hepatitis C virus (HCV) has not been shown to result in acute hepatic failure and hepatitis E virus (HEV) has predominantly been associated with fulminant hepatitis among pregnant women. Methods: Using polymerase chain reaction to detect HCV and HEV genomes, four-antigen radioimmunoblot assay (4-RIBA) to measure anti-HCV antibodies, and enzyme-linked immunosorbent assay (ELISA) to detect anti-HEV immunoglobulin M (IgM) antibodies, 17 patients with sporadic fulminant or subfulminant hepatitis of presumed NANB viral etiology were studied. Results: The diagnosis of acute NANB viral hepatitis was made based on clinical information, serological tests, biochemical profiles, and pathological features. All 17 patients were negative for anti-HEV IgM antibodies and HEV RNA in either serum and/or liver. HCV RNAs were detected in 2 patients although anti-HCV antibodies were negative in all of them. Conclusions: It is shown that HCV is infrequently associated with and HEV is not an identifiable cause of presumed NANB fulminant or subfulminant hepatitis in this patient population. Although further studies will be required for identification of the causative agent, it is possible that another agent is responsible for the occurrence of sporadic NANB fulminant or subfulminant hepatitis.

Perspective study of the antibody response to hepatitis C virus (HCV) antigens in acute nonA-nonB viral hepatitis

Perspective study of the antibody response to hepatitis C virus (HCV) antigens in acute nonA-nonB viral hepatitis

Non-A non-B hepatitis virus antigen peptide; used for diagnosis, recombinant vaccine and antibody production

Non-A non-B hepatitis virus antigen peptide; used for diagnosis, recombinant vaccine and antibody production

Viral hepatitis

Hepatitis may be caused by hepatitis A virus, hepatitis B virus, hepatitis C virus (classic non-A non-B viral hepatitis), hepatitis D virus (delta agent), and hepatitis E virus (epidemic non-A non-B viral hepatitis). Cytomegalovirus, Epstein-Barr virus, and herpes simplex virus may also occasionally cause hepatitis. Some forms of hepatitis carry the risks of chronic infection, cirrhosis, or hepatocellular carcinoma. Treatment options for viral hepatitis are limited and, in many cases, still under investigation. Prophylaxis is available for many forms of hepatitis and should be offered to those at risk.

Successful Bone Marrow Transplant and Re‐Growth of Hair in a Patient with Posthepatic Aplastic Anemia Complicated by Alopecia Totalis

Bone marrow transplant was performed in a child with posthepatic aplastic anemia complicated by alopecia totalis. The procedure was successful, as the graft was apparently "taken" by the recipient and hair started to grow on the head. The hair has not been lost since, and is still growing as of the date of this report. Although nonA nonB hepatitis virus was found to be the cause of hepatitis in this patient, the reason for the alopecia totalis which developed 7 years previously is unclear. The postoperative growth of the hair was attributed to restoration of normal immunologic function through bone marrow transplant.

A human T-cell clone cytotoxic for hepatocytes from patients with chronic non-A, non-B hepatitis

A human T-cell clone (TA-NB-2) which could lyse hepatocytes from patients with chronic non-A, non-B (NANB) hepatitis was established (Proc Natl Acad Sci USA 1989;86:2883-2887). TA-NB-2 cells belonged to CD3+ CD8+ cytotoxic T lymphocytes, and recognized the target hepatocytes by T-cell receptor without restriction by major histocompatibility complex (MHC) antigens. TA-NB-2 cells significantly lysed hepatocytes from 22 of 23 patients with chronic NANB hepatitis, whereas they lysed hepatocytes from only one of 17 control patients with chronic type B hepatitis, acute hepatitis B or acute hepatitis A. TA-NB-2 cells also significantly lysed hepatocytes from 4 of 5 patients with autoimmune liver disease. The results suggest that TA-NB-2 cells specifically recognize a NANB hepatitis-related antigen expressed on NANB hepatitis virus-infected hepatocytes by T-cell receptor in non-MHC-restricted manner. The results also suggest that most, if not all, cases of chronic NANB hepatitis are caused by one agent and that a portion of cases of autoimmune liver disease may be induced by infection with a NANB hepatitis virus.

Chronic Non-A, Non-B Hepatitis in Pregnancy

11 women with chronic non-A, non-B hepatitis (NANBH) were studied during 14 pregnancies. All women remained well, without signs of deterioration of liver function. On the contrary, serum transaminase levels were significantly lower in the latter part of the pregnancy compared to before and after. 12 children were born at full term. One child was born preterm and 1 child was stillborn after 36 gestational weeks. During follow-up, 8 of the children had elevated alanine amino transferase (ALT) levels in serum at least at one sampling occasion. Four children had ALT elevation in consecutive blood samples, 2 of whom had a longlasting ALT elevation, probably due to mother-to-infant transmission of NANBH virus(es).

Detection of antibody against antigen expressed by molecularly cloned hepatitis C virus cDNA: application to diagnosis and blood screening for posttransfusion hepatitis.

A cDNA clone has been derived from the plasma of a chimpanzee with chronic non-A, non-B viral hepatitis (NANBH). We have assayed for antibodies reacting with the encoded antigen in sera from posttransfusion hepatitis patients (643 samples from 23 patients) and their corresponding donors collected during the past 10 years in Japan. The antibody was detected in 15 out of 17 (88.2%) posttransfusion NANBH (PT-NANBH) patients whose sera over time displayed multiple alanine aminotransferase (ALT) peaks. In general, the antibody was detected after several peaks of serum ALT elevations and, once detected, it persisted for years. In contrast to the patients of chronic hepatitis, the antibody was barely detected in patients with a single episode of ALT elevation (1 out of 6). Of the 15 well-defined cases of PT-NANBH that showed multiple ALT peaks and hepatitis C virus seroconversions, 11 (73.3%) were shown to be transfused with at least one unit of blood positive for the antibody. The retrospective analysis showed that all tested donor blood found to be positive for the antibody had been transfused to recipients who afterwards developed NANBH. These data strongly suggest that the cloned cDNA originated from an etiological agent of NANBH termed the hepatitis C virus. Furthermore, the present study demonstrates that had the screening been done with the anti-hepatitis C virus assay, 11 out of 17 (64.7%) cases of chronic PT-NANBH and 1 out of 6 (16.6%) acute PT-NANBH would have been prevented. The antibody assay thus can be used for diagnosis and blood screening for PT-NANBH.

4871659 Reagent for detecting non-A, non-B viral hepatitis (NANBH) and an immunoenzymatic method for detecting NANBH antigens in fecal extracts : Jacques Pillot, Gif Sur Yvette, France assigned to Institut Pasteur

4871659 Reagent for detecting non-A, non-B viral hepatitis (NANBH) and an immunoenzymatic method for detecting NANBH antigens in fecal extracts : Jacques Pillot, Gif Sur Yvette, France assigned to Institut Pasteur

Aetiology and outcome of acute viral hepatitis in pregnancy

The aetiologic types of sporadic acute viral hepatitis in 169 pregnant women were compared with those of 70 non-pregnant women and 287 adult men. The majority of pregnant women (87.6%) came with acute hepatitis in the last trimester of pregnancy. Non-A, non-B (NANB) hepatitis accounted for 81.6% of hepatitis during pregnancy in comparison with 48.6% in non-pregnant women and 57.1% in adult men. Hepatitis A was extremely uncommon during pregnancy. Hepatitis B infection accounted for 17% of all cases in pregnant women compared with 45% in controls. Acute viral hepatitis in pregnancy had a poor outcome as assessed by maternal and/or fetal mortality (28.5%). The outcome was equally bad in hepatitis NANB and hepatitis B. Pregnant women generally had significantly lower immunoglobulin levels in comparison with non-pregnant women. In acute NANB hepatitis during pregnancy, serum IgG and IgM levels were lower and higher, respectively, compared with those in non-pregnant women and pregnant women with acute hepatitis B. It is suggested that an immune suppression during pregnancy might be responsible for increased susceptibility to acute NANB viral hepatitis, which, by itself, seems to induce only a transient acute phase IgM response.

Chronic Non-A, Non-B Hepatitis in Pregnancy: Outcome and Possible Transmission to the Offspring

11 women with chronic non-A, non-B hepatitis (NANBH) were studied during 14 pregnancies. All women remained well, without signs of deterioration of liver function. On the contrary, serum transaminase levels were significantly lower in the latter part of the pregnancy compared to before and after. 12 children were born at full term. One child was born preterm and 1 child was stillborn after 36 gestational weeks. During follow-up, 8 of the children had elevated alanine amino transferase (ALT) levels in serum at least at one sampling occasion. Four children had ALT elevation in consecutive blood samples, 2 of whom had a longlasting ALT elevation, probably due to mother-to-infant transmission of NANBH virus(es).

PHOTOCHEMICAL DECONTAMINATION OF BLOOD COMPONENTS CONTAINING HEPATITIS B AND NON-A, NON-B VIRUS

Diluted plasma samples containing 102, 103, 104, and 105 chimpanzee infectious doses (CID) of a human non-A, non-B hepatitis virus (NANBV) were treated with a combination of two psoralen compounds, 4'-aminomethyl-4,5',8-trimethylpsoralen and 4,5',8-trimethylpsoralen, and exposed to long wavelength ultraviolet. Each dilution was then transfused into one of four chimpanzees. In a second experiment, three samples containing 1045 CID of hepatitis B virus (HBV) and two samples containing 104 CID of NANBV were treated with 8-methoxypsoralen (8-MOP) and ultraviolet irradiation. Two chimpanzees were each transfused with both a treated HBV and a treated NANBV sample. The third chimpanzee was inoculated with a treated HBV sample alone. In the six months after inoculation none of the animals showed biochemical or histological evidence of hepatitis. In experiments involving NANBV inocula, the susceptibility of the animals was confirmed by subsequent challenge with untreated NANBV. Factor VIII concentrate containing virus and photochemically treated as in the first experiment retained an average of 91% of its activity while that in the second experiment retained 94% of its activity.