The natural history of hepatitis c virus hcv infection. Structure and functions of hepatitis c virus proteins. Author summary cd81 is a cell membrane protein, which functions as entry factor for hepatitis c virus hcv and malaria sporozoites in the human liver. Making use of a recently identified hepatitis c virus hcv isolate jfh1 that can be propagated in tissue. The core protein of hepatitis b virus encompasses b and tcell immunodominant epitopes and subdivided into two domains. Due to its complexity and presumed essentiality for viral replication, the helicase is an. All genotypes of hcv appear to cause some degree of steatosis. A large proportion of patients infected by hcv develop liver cirrhosis or cancer. Comparisons between the cterminal halves ofpoliovirus vp1and havvp1showamarkeddecrease in surface profile. Infectious hbv has a spherical structure consisting of hepatitis b surface antigen hbsag that envelops the viral nucleocapside, which is formed by the. For 30 of the 33 interacting proteins it was unclear, whether they played a role in hepatitis c virus infection. The structures were aligned for best overlap of residues 525.
Mutations of the core gene may change the conformation of the core protein or cause alteration of important epitopes in the host immune response. Hepatitis c virus and hepatitis b can make an infected person very sick and they are risk factors for liver cancer, liver disease, liver failure, and liver damage. Katherine crowder, andrew macdonald, kevin poupard, andrew street, david rowlands and mark harris hepatitis c virus hcv is an increasingly important cause of liver disease. Here, we use high resolution quantitative proteomics to. To gain further insight into the function of ns5a, we screened a human fetal liver cdna library for its interacting proteins using the yeast twohybrid system. The most widely quoted data on the prevalence of hcv in the united states comes from the third national health and nutrition examination survey nhanes, a national survey of a representative sample of noninstitutionalized civilian americans conducted between 1988 and 1994. Within the polyprotein encoded by hepatitis c virus hcv, the minimum components for viral rna replication lie in the ns35b region while virion assembly requires expression of all virus components. Surface probability profiles comparing havvp15 to 114 with poliovirus type 1 mahoneystrain vp11 to 110 12, 17.
To assess the specificity of our ebv interactome data set, interactions identified by y2h were assayed by coaffinity purification coap using glutathione beads and expression of gst and egfp fusion proteins in 293 cells. A characteristic of many positivestrand rna viruses is that, whilst replication of the viral genome is dependent on the expression of the majority of nonstructural proteins in cis, virus particle formation can occur when most or all of the structural proteins are coexpressed in trans. Approximately 180 million people or 3% of the worlds population are infected with the virus. The majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. Human hepatitis b virus hbv causes acute and chronic inflammation of the liver. Scissors indicate cleavages by the endoplasmic reticulum er signal peptidase. Hepatitis c virus hcv causes acute and chronic liver disease in humans, including chronic hepatitis. Structure and functions of hepatitis c virus proteins 1 its immensely important to begin read the intro section, next to the short discussion and find out each of the subject.
Currently, it remains enigmatic how cd81 guides the entry process of both pathogens and whether it functions in a similar way during liver cell invasion of hcv and malaria parasites. A thesis submitted in partial fulfillment of the requirements for the degree of master of science in the department of molecular biology and microbiology. Easl 2017 clinical practice guidelines on the management. Abstract hepatitis c virus nonstructural protein ns5a plays an important role in viral replication and various cellular events. Lipid droplets are intracellular organelles involved not only in lipid storage but also in cell signalling and the regulation of intracellular vesicular trafficking.
Structural biology of the hepatitis c virus proteins. In hcv genotype 3infected patients, the etiology of steatosis appears to be closely correlated with unknown viral factors that increase intracellular lipid levels. The flaviviridae family includes yellow fever virus, west nile virus, and dengue virus. Pdf structure and functions of hepatitis c virus proteins. Reviews structural proteins of hepatitis c virus tatsuo miyamura and yoshiharu matsuura h epatitis c virus hcv is the most import ant causative agent of elusive hepatitis, previously called nona, nonb hepatitis, which affects about one million people per year world wide. Besides, the terminal protein has also been shown to inhibit host cellular response to interferon.
Structure and functions of hepatitis c virus proteins 1 by. Hepatitis c virus hcv, a member of flaviviridae, is a causative agent of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma hcc 1, 2. After initial infection with hbv, most patients successfully develop immunity to clear the infection 8790%, but the rest become chronic hbv carriers. The hcv particles are spherical and heterogenous in size, typically ranging 4080 nm in diameter. Structural proteins of hepatitis c virus sciencedirect. A critical role of hepatitis b virus polymerase in. A description of total protein test, a test for liver function part of the just diagnosed lesson for patients, from the va national viral hepatitis and liver disease program. Despite the discovery of hcv over 15 years ago, our knowledge.
Steatosis and liver cancer in transgenic mice expressing. Hepatitis c virus has an outer envelope containing two viral envelope proteins. Hepatitis c virus enters liver cells using the cd81. The pathogenesis of inflammation and fibrosis in chronic hepatitis c virus hcv infection remains unclear. When the acute infection becomes chronic, there is a progressive impairment in hbv speci. Structure and function of hepatitis c virus ns3 helicase.
Sciencefrontier structural biology of hepatitis c virus. Individual proteins within the polyprotein and their functions in the viral. Function hepatitis c virus hcv is an enveloped, positivestrand rna virus classified in the hepacivirus genus within the flaviviridae family. Hcv infection frequently causes chronic hepatitis, which often leads to the development of liver cirrhosis and hepatocellular carcinoma after a long period. Patients who are infected with hbv as neonates or young children usually become. The hepatitis c virus hcv genome contains an internal ribosome entry site ires followed by a large open reading frame coding for a polyprotein that is cleaved into 10 proteins.
Viral proteins and their functions in hcv life cycle. Chronic hbv infection progresses through distinct disease phases that are strongly associated with age. The structural proteins, which form the viral particle, include the core protein and the envelope glycoproteins e1 and e2. Apply for and manage the va benefits and services youve earned as a veteran, servicemember, or family memberlike health care, disability, education, and more. The nonstructural proteins of the hepatitis c virus. A, superimposition of calculated average structures obtained in the presence of 100 m m sds red, 100 m m dpc green, and 50% tfe light gray. Hepatitis b is mainly sexually transmitted, but may also be passed from mother to baby during pregnancy or childbirth. Both hepatitis b and hepatitis c are commonly spread through infected blood such as may occur during needle sharing by intravenous drug users. Expression and purification of hepatitis b surface antigen. Translation of the f protein of hepatitis c virus is. Specific polymorphisms in hepatitis c virus genotype 3. Hepatic inflammation mediated by hepatitis c virus core. Steatosis is a common histological finding and a poor prognostic indicator in patients with hepatitis c virus hcv infection.
Hepatitis c virus hcv encodes a single polyprotein, which is processed by cellular and. By testing every single one of the 33 proteins for their role in infection, the researchers found two novel proteins, which are important for virus entry. The transcriptional function of the hepatitis b virus x. Both the vaccine and the diagnostic kits depend on using the hepatitis b. Hepatitis c virus hcv infects millions of people worldwide and is one of the leading causes of liver damage. Hepatitis b virus hbv is the most frequent pathogen that infects humans and chimpanzees, causing acute and chronic hepatitis or liver inflammation. Infection of hepatitis c virus hcv 1 is estimated to occur in about 3% of the worlds population. Structural and functional studies on the terminal protein. Hepatitis c virus nonstructural protein ns5a interacts. Structure and function of the membrane anchor domain of. Role of hepatitis c virus proteins c, ns3, ns5a in. Until recently, studies of hcv have been hampered by the lack of a productive cell culture system. Epsteinbarr virus and virus human protein interaction maps. Hbv is one of the smallest enveloped dna viruses and the prototype member of the family of hepadnaviridae.
Hepatitis c virus core protein, lipid droplets and. Structural biology of hepatitis c virus wiley online library. Since hcv does not carry any known oncogene, it is thought that interaction between virally encoded proteins and host proteins is responsible for carcinogenesis. Hepatitis c virus hcv infection afflicts more than 170 million people worldwide, with the great majority of patients with acute hepatitis c developing chronic hcv infection. It can ultimately result in liver cirrhosis, hepatic failure or hepatocellular carcinoma, which are responsible for hundreds of thousands of deaths each year. Understanding the structure and function of hcv proteins in the viral lifecycle is of paramount importance to fuel new drug development. Hepatitis c virus infection is a major health problem all over the world. Hepatitis c virus nonstructural 5a protein inhibits. Hepatitis c virus nonstructural proteins in the probable. Teruhime otoguro, tomohisa tanaka, hirotake kasai, atsuya yamashita and kohji moriishi, inhibitory effect of presenilin inhibitor ly411575 on maturation of hepatitis c virus core protein, production of the viral particle and expression of host proteins involved in pathogenicity, microbiology and immunology, 60, 11, 740753, 2016. Structural and functional studies on hepatitis c virus non.
Here, we have employed complementation systems to examine the role that hcv polyprotein precursors play in rna replication and virion assembly. Specific targeting of hepatitis c virus core protein by an. Structural and functional studies on hepatitis c virus nonstructural proteins. Hepatitis c virus hcv encodes a single polyprotein, which is processed by cellular and viral proteases to generate 10 polypeptides. Both gstx and egfpy proteins were sufficiently well expressed in 293 cells to enable testing of 32 pairs. Prior to 1992, blood transfusion was a risk for contracting hepatitis c infection. New insights into protein synthesis and hepatitis c infections. It is distributed worldwide and associated with high mortality and morbidity rates. Hepatitis c virus helicase activity has been mapped to the coohterminal 450 residues of the ns3 protein. Hepatitis c virus hcv is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. Hepatitis b virus x protein induces hepatic steatosis by. Pdf great progress has been made over the past years in elucidating the structure and function of the hepatitis c virus hcv proteins, most.
The molecular mechanisms underlying interferon resistance are poorly understood. Topology and membrane rearrangements of the hcv protein ns4b abstract hepatitis c virus hcv is a major cause of chronic liver disease and viral hepatitis around the world. Hepatitis b and c are bloodborne infections, while hepatitis a is easier to catch, but less serious. Structural biology of hepatitis c virus penin 2004 hepatology. Expression of hepatitis c virus hcv structural proteins. Great progress has been made over the past years in elucidating the structure and function of the hepatitis c virus hcv proteins, most of which are now actively being pursued as antiviral targets. Structural and functional properties of the hepatitis c virus. Hepatitis c is a liver infection that can lead to serious liver damage. Hepatitis b is a liver disease primarily caused by hepatitis b virus hbv infection. Expression of the structural proteins enhances a low background of steatosis in c57bl6 mice, while additional low level expression of nonstructural proteins increases the risk of cancer.
Underneath the membrane is a layer of the viral core protein, which binds to the viral genome forming the. Pdf since its discovery in 1988, the hepatitis c virus hcv has become a hot topic of research by many groups around the world. Infection with hcv is strongly correlated with an increased risk of steatosis, or fatty liver disease, which is caused by a buildup of fat deposits in hepatocytes. Orfs that encode the viral surface proteins, core protein, viral polymerase and x protein hbx2. Expression of hepatitis c viral nonstructural 3 antigen. Hepatitis b virus x protein induces hepatic steatosis by enhancing the expression of liver fatty acid binding protein yunli wu, a,b xiane peng, a,c yibing zhu, a xiaoli yan, wannan chen, a,b xu lin. Genetic complementation of hepatitis c virus nonstructural. Structural and functional genome organization and life cycle of. The role of mutations in core protein of hepatitis b virus. Variable level expression of hepatitis c virus core.
Expression of hepatitis c viral nonstructural 3 antigen in transgenic chloroplasts by anubhuti bhati m. Recent basic studies have suggested that interactions between hepatitis c virus hcv core protein and lipid droplets are required for the hcv infection cycle. Interaction of hepatitis c viral proteins with cellular. Hbv infections can be avoided by the administration of the currently available vaccine and can be easily diagnosed through commercially available kits. This is essential to understanding the mechanisms underlying viral protein function and to identifying molecular targets for specific inhibitors i. Transgenic mice with constitutive hcv core overexpression display steatosis only. Introduction hepatitis c virus hcv, a major cause of chronic hepatitis, may lead to cirrhosis and to hepatocellular carcinoma houghton 1996. Among these viral proteins, the surface proteins form the viral envelope, the core protein comprises the nucleocapsid and the viral polymerase is necessary for replication of the virus 1,2.
The structure and function of particular viral structural core, e1, e2 and nonstructural ns2, ns3, ns4, ns5 proteins and noncoding regions known to date are described. Interferoninduced activation of the jakstat signal transducer and activator. Protein complex for hepatitis cvirusentry in liver cells. Induction ofhepatitis a virusneutralizing antibody bya. The correlation coefficient r for the comparison shownis 0. Hepatitis b virus hbv hepatitis b was recognized as a disease in ancient times, but the virus itself was identified not until 1965.