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Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity. Here, we show that hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 IFN responses by targeting the 3ABC precursor of its [3C.sup.pro] cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway. The 3ABC cleavage of MAVS requires both the protease activity of [3C.sup.pro] and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature [3C.sup.pro] protease is incapable of MAVS proteolysis. HAV thus disrupts host signaling by a mechanism that parallels that of the serine NS3/4A protease of hepatitis C virus, but differs in its use of a stable, catalytically active polyprotein processing intermediate. The unique requirement for mitochondrial localization of 3ABC underscores the importance of mitochondria to host control of virus infections within the liver. hepatitis virus | interferon regulatory factor 3 | interferon-beta | melanoma differentiation associated gene 5 | mitochondrial antiviral signaling protein

The impact of naturally occurring variants near the protease inhibitor binding site is studied by their identification based on sequence alignment of the protease region from genotype 1-3 sequences found in the three genotypes of the hepatitis virus C (HCV). Substitution experiments reveal that a protease inhibitor BILN 2061 confers greater potency against genotype 1 of HCV, rendering it more sensitive to variations near the binding site, while VX-950 is equally active on all 3 genotype proteases.

Chronic hepadnavirus infections cause liver damage with ongoing death and regeneration of hepatocytes. In the present study we set out to quantify the extent of liver turnover by measuring the clonal proliferation of hepatocytes by using integrated viral DNA asa genetic marker for individual hepatocyte lineages. Liver tissue from woodchucks with chronic woodchuck hepatitis virus (WHV) infection was assayed for randomly integrated viral DNA by using inverse PCR. Serial endpoint dilution of viral-cell junction fragments into 96-well plates, followed by nested PCR and DNA sequencing, was used to determine the copy number of specific viral cell junctions as a measure of the clonal distribution of infected cell subpopulations. The results indicated that the livers contained a minimum of 100,000 clones of >1,000 cells containing integrated DNA, representing at least 0.2% of the hepatocyte population of the liver. Because cells with integrated WHV DNA comprised only 1-2% of total liver cells, it is likely that the total number of ciones far exceeds this estimate, with as muchas one-half of the liver derived from high copy clones of > 1,000 cells. It may be inferred that these clones have a strong selective growth or survival advantage. The results provide evidence for a large amount of hepatocyte proliferation and selection having occurred during the period of chronic WHV infection ([approximately equal to] 1.5 years) in these animals. endpoint dilution | inverse PCR | hepatocyte ciones

The affective disturbances and significant psychomotor slowing in HIV-positive patients are examined. HIV and hepatitis virus (HCV), which cause cognitive and motor dysfunction affect the central nervous system.

In this review, recently identified hepatitis viruses (hepatitis C, hepatitis D, hepatitis E, hepatitis F, hepatitis G, transfusion transmissible virus) are described, and the implications for paediatric liver disease discussed. [...]

Research has been conducted on the hepatitus C virus (HCV) NS3 protein. The mechanism of NS3 helicase activity has been examined by means of 2'-O-methyl RNA substrates.

Hybrids of tobacco mosaic virus (TMV) were constructed with the use of fusion to the coat protein peptides of 10 or 15 amino acids, containing the 5B19 epitope from the spike protein of murine hepatitis virus (MHV) and giving rise to TMV-5B19 and TMV-5B19L, respectively. The TMV hybrids were propagated in tobacco plants, and the virus particles were purified, Immunogold labeling, with the use of the monoclonal MAb5B19 antibody, showed specific decoration of hybrid TMV particles, confirming the expression and display of the MHV epitope on the surface of the TMV. Mice were immunized with purified hybrid viruses after several regimens of immunization. Mice that received TMV-5B19L intranasally developed serum IgG and IgA specific for the 5B19 epitope and for the TMV coat protein. Hybrid TMV-5B19, administered by subcutaneous injections, elicited high titers of serum IgG that was specific for the 5B19 epitope and for coat protein, but IgA that was specific against 5B19 was not observed. Mice that were immunized with hybrid virus by subcutaneous or intranasal routes of administration survived challenge with a lethal dose (10 x [LD.sub.50]) of MHV strain JHM, whereas mice administered wild-type TMV died 10 d post challenge. Furthermore, there was a positive correlation between the dose of administered immunogen and protection against MHV infection. These studies show that TMV can be an effective vaccine delivery vehicle for parenteral and mucosal immunization and for protection from challenge with viral infection.

To investigate host and viral mechanisms determining hepadnaviral persistence and hepatocarcinogenesis, we developed a mouse model by transplanting woodchuck hepatocytes into the liver of mice that contain the urokinase-type plasminogen activator transgene (uPA) and lack mature B and T lymphocytes due to a recombination activation gene 2 (RAG-2) gene knockout. The woodchuck hepatocytes were transplanted via intrasplenic injection and were found to integrate into the recipient mouse liver cord structure. Normal adult woodchuck hepatocytes proliferated and reconstituted up to 90% of the uPA/RAG-2 mouse liver. uPA/RAG-2 mice containing woodchuck hepatocytes were infectable with woodchuck hepatitis virus (W and showed WHV replication for at least 10 months with titers up to 1 x [10.sup.11] virions per ml in the peripheral blood. WHV-infected hepatocytes from chronic carrier woodchucks also established a persistent infection in uPA/RAG-2 mice after an 8- to 12-week lag period of viremia. Although WHV envelope, core, and X proteins were produced in the uPA/RAG-2 mice, no inflammatory host immune response was observed in the liver of WHV-replicating mice. A first antiviral test demonstrated a greater than four orders of magnitude drop in WHV titer in response to interferon [Alpha] treatment. WHV replication was up-regulated by dexamethasone treatment. Comparison of precancerous lesions in donor woodchucks versus recipient uPA/RAG-2 mice revealed an enrichment of dysplastic precancerous hepatocytes in transplanted mice. Clonal amplification of hepatocytes from a woodchuck with hepatocellular carcinomas was demonstrated by the detection of unique WHV DNA integration patterns in hepatocellular carcinomas that arose in uPA/RAG-2 mice. In the absence of B or T cell-mediated immune responses, WHV establishes a persistent noncytotoxic infection of woodchuck hepatocytes in uPA/RAG-2 chimeric mouse livers. Further studies of the kinetics of hepadnavirus infection and replication in quiescent and proliferating hepatocytes should increase our understanding of hepadnavirus spread and aid in the design of therapies to block or cure persistent infection.

Human foamy virus (HFV) is the prototype of the Spumavirus genus of Retroviridae. In all other retroviruses, the pol gene products, including reverse transcriptase, are synthesized as Gag-Pol fusion proteins and are cleaved to functional enzymes during viral budding or release. In contrast, the Pol protein of HFV is translated from a spliced messenger RNA and lacks Gag domains. Infectious HFV particles contain double-stranded DNA similar in size to full-length provirus, suggesting that reverse transcription has taken place in viral particles before new rounds of infection, reminiscent of hepadnaviruses. These data suggest that foamy viruses possess a replication pathway containing features of both retroviruses and hepadnaviruses but distinct from both., The retroviral replication pathway is understood in great detail, and it has been assumed that all members of the Retroviridae family use the same mechanisms for assembly and reverse transcription [...]

The viral membrane glycoproteins M and S of mouse hepatitis virus interact in the infected cells leading to heteromultimeric complexes during viral assembly, which occurs in the smooth membranes of the intermediate endoplasmic reticulum-to-Golgi compartment. When other coronaviral proteins are absent M/S complexes are generated. The budding position is not determined by the envelope glycoprotein complexes.

Representational difference analysis, used to clone nucleotide sequences present in the plasma from a tamarin infected with the GB hepatitis agent reveals the presence of flavivirus-like genomes in the GB agent. Flaviviruses are viruses that are enveloped and contain one positive-sense genomic RNA molecule. The two viruses may have different origins, one may have the human GB as its source, while the other probably originates from tamarins during the passage of the GB agents in tamarins.

Changes in human ecology influenced the medical impact of each of the five hepatitis viruses from different viral families on the human population. These five distinct viruses which cause viral hepatitis affect the liver, but differ in all their other activities.

Streptolysin O (SLO) diffusion experiments on mouse L cells facilitated the examination of membrane composition of the interface between endoplasmic reticulum (ER) and Golgi complex, rendering the characterization of the budding protein of mouse hepatitis virus (MHV). These studies indicated the adequacy of a single vesicular transport step for cellular trafficking from rough ER to Golgi complex. Interdomain between ER and Golgi complex is ER-specific and spans the region between ER and first cisterna on the cis side of the Golgi stack.

The applicability of the polymerase chain reaction (PCR) to detect Hepatitis E virus (HEV) in sewage treatment plants and establish the prevalence of hepatitis viral diseases in a population is studied. An epidemic of HEV infections due to a lack of adequate public sanitations has increased in many developing countries. Specific DNA amplification by PCR in combination with slot-blot hybridization was used to indicate that HEV was present in the three sewage samples of the inlets and outlets.

A mutation analysis was conducted on themouse hepatitis virus receptor (MHVR) to determine the domains required for binding to MHV and for functional MHVR activity. The results showed that MHV strain A59 and anti-receptor monoclonal antibody interacted with the N-terminaldomain of MHVR. Interactions were also detected for the 24 amino acids between the first and second domains and an immunoglobulin-like domain.

RNA-dependent RNA polymerase, papain-like cysteine protease domain remotely associated with the putative papain-like protease of rubella virus (Rubv), a domain of unidentified function near the papain-like protease domains in the polyproteins of animal positive-strand RNA viruses methyl transferase and RNA helicase, were identified through the computer assisted comparison of the non-structural polyprotein of hepatitis E virus (HEV) with proteins of other positive strand RNA viruses. In the alpha-like super group of positive strand RNA viruses, HEV, Rubv and beet necrotic yellow vein virus form a unique monophyletic group.

A panel of 14 ground squirrel hepatocellular carcinoma (HCC) was characterized with respect to the presence of ground squirrel hepatitis virus (GSHV) DNA and potential alterations of myc genes. In contrast with the woodchuck hepatitis virus, integrated GSHV DNA was detected in only a few tumors and did not result in insertional activation of myc genes. However, a high frequency of c-myc amplification in ground squirrel HCCs was observed.

The hepatitis viruses continue to be the focus of intensive research. In 1995, a new virus was discovered that is related to hepatitis C virus but does not seem to cause serious disease. Most infants are now being vaccinated against hepatitis B but there are still many carriers who must be treated. Helicobacter pylori is known to be responsible for peptic ulcer disease and some types of gastrointestinal cancers. The US Preventive Services Task Force recommends screening all people over 50 for colorectal cancer but it is not clear whether this will lower mortality rates.

The editors of JAMA reprint one of the first articles reporting the development and testing of a vaccine against hepatitis B. Viral antigens were purified from blood samples from infected patients. The experimental vaccine was tested in chimpanzees, guinea pigs and marmosets. All these animal groups produced antibodies against the virus after vaccination with the antigens. Three doses of the vaccine completely protected chimpanzees from infection with human hepatitis virus., A highly purified and inactivated vaccine was made of hepatitis B virus surface antigen. The vaccine was tested exhaustively for safety by ordinary procedures and additionally In chimpanzees and marmosets. It was highly potent and induced antibody in guinea pigs, grivet monkeys, and chimpanzees after three doses of vaccine were given subcutaneously. Chimpanzees given three doses of vaccine were protected against challenge with 1,000 chimpanzee-infectious doses of live human hepatitis B virus given Intravenously in controlled studies. Tests of the vaccine for control of hepatitis B in man are to be carried out. (JAMA 235:2832,2834, 1976)

Mitogen-Induced Replication of Woodchuck Hepatitis Virus in Cultured Peripheral Blood Lymphocytes A NUMBER OF ACUTE AND CHRONIC viral infections involve a lymphatic phase with early replication at the site of [...]

Putative Reverse Transcriptase Intermediates of Human Hepatitis B Virus in Primary Live Carcinomas HUMAN HEPATITIS B VIRUS (HBV) CONTAINS A DNA genome but resembles retroviruses (i) in its mode of [...]

HALFWAY TO HEPATITIS CURE A drug to counter viral hepatitis, which can cause fatal liver damage, is in the process of being licensed for treatment after successful clinical trials. The [...]