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Hepatitis C Virus (HCV)

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HCV taxonomy

Viruses - ssRNA viruses - ssRNA positive-strand viruses, no DNA stage - Flaviviridae - Hepacivirus - Hepatitis C virus

Synonyms

HCV is the only member of Hepacivirus genus. This genus belongs to Flaviviridae family, which includes human and animal pathogens (yellow fever, dengue, West Nile and tick-borne encephalitis, human flaviviruses, cattle pestiviruses and simian GB-virus B).

GB virus B is the most closely related to HCV: its taxonomy

Peculiarities of HCV that set it apart from the other Flaviviruses:

HCV isolates from the serum of patients fall into three major categories, depending on the degree of sequence divergence of HCV RNA: genotypes, subtypes and isolates. There are six major HCV genotypes differing in their nucleotide sequence by 30-35%, and a seventh genotype has been discovered in 2008. Within HCV genotype, several subtypes (designated as a, b, c, etc.) can be defined that differ in their nucleotide sequence by 20-25%.

All currently recognized HCV genotypes are hepatotropic and pathogenic. Different genotypes vary in their infectivity and pathogenicity, thereby influencing the rate of progression to cirrhosis and the risk of liver cancer.

The highest sequence variability concentrated in hypervariable region of E1 and E2 glycoprotein. The lowest sequence variability between genotypes is found in the 5' untraslated region (UTR) which contains specific sequences and RNA secondary structures that are required for replication and translation functions (internal ribosomal entry site (IRES)).

HCV has a high replication rate but lacks a proofreading mechanism, leading to the production of multiple viral variants in single patient. These variants are referred to as viral 'quasispecies' and diverge 1-5% in nucleotide sequence.

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Definitions

Hepatitis C Virus (HCV) is human-specific viral pathogen of the liver. HCV represents a serious health problem worldwide as approx. 130-170 million people (2% of the world population) are infected.

The liver is the largest glandular organ of the human body and it is also the only organ that is able to regenerate to form new tissue. It is located in the upper right quadrant of the abdominal cavity just beneath the diaphragm and is comprised of four unequally sized lobes and two ligaments for support. Its highly vascular nature gives it a fleshy red coloring. Hepatocytes (hepatic cells) are the basic metabolic cells of the liver. HCV infection is mainly restricted to hepatocytes. Among important functions of the liver are detoxification of harmful chemicals and metabolites from the blood; storage of vitamins, such as vitamins A, D, K, and B12, and many minerals; conversion of ammonia into urea and many others. Without the liver a person would not be able to maintain the proper levels of glucose in the blood needed to produce the key amino acids required to make proteins, convert glucose to glycogen, and generate cholesterol.

Hepatitis means inflammation of the liver. It can be caused by toxins (such as alcohol), by some diseases, and bacterial and viral infections. The infection caused by HCV is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis) and advanced scarring (cirrhosis), which is generally apparent only after many years. In some cases, individuals with cirrhosis go on to develop liver failure or other complications of this advanced scarring, including liver cancer (hepatocellular carcinoma (HCC)).

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Discovery & timeline

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Epidemiology

Genotype 1a and 1b is common in Western Europe. Genotype 3 is most frequent in the India, Nepal and Pakistan. Genotype 4 is the most common genotype in Africa and the Middle East. Genotype 5 is found in South Africa. Genotype 6 is found in Hong Kong and Southeast Asia. Genotype 3a has a high prevalence worldwide, infecting up to 50% of patients in several European countries as well as a high percentage of HCV-infected individuals in many highly populated countries in Asia (e.g. India). In Pakistan the major HCV genotype is 3a followed by 3b and 1a. The prevalence rate was estimated to be 5.3% in Africa (31.9 million cases), 4.6% in the Eastern Mediterranean region (21.3 million cases), 3.9% in the West Pacific region (62.2 million cases), 2.15% in Southeast Asia (32.3 million cases), 1.7% in the Americas (13.1 million cases) and 1.03% in Europe (8.9 million cases).

The prevalence of chronic infection in the United States is 1.8% while Canada's rate of infection is estimated at 0.1-0.8%.

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Structure

The hepatitis C virus particle is about 50-60 nm in size. The envelope is made of a lipid bilayer in which two envelope proteins, E1 and E2, are anchored. The envelope surrounds the nucleocapsid, composed of multiple copies of a small basic protein (core or C). Nucleocapsid encloses RNA genome. The genome is approximately 9.6 kb in length, and is a single positive-sense strand with a single open reading frame (ORF) encoding a polyprotein of about 3,000 amino acids. The ORF is flanked by 5' and 3' untranslated regions (UTRs). Both UTRs bear highly conserved RNA structures that are essential for both polyprotein translation and genome replication. The HCV ORF contains 9,024 to 9,111 nt depending on the genotype. The ORF encodes at least 11 proteins, including three structural proteins (C or core, E1 and E2), a small protein (p7), six nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B), and the so-called "F" protein that results from a frameshift in the core coding region.

Putative HCV virion particle

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Transmission

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Disease progression

Symptoms of acute hepatitis manifested in rare patients are usually mild. Jaundice is present in less than 2%. The other symptoms are similar to those in other forms of acute viral hepatitis, including malaise, nausea and pain right upper quadrant. Fulminant hepatic failure due to acute HCV infection is very rare.

After transmission the HCV infection follows different course depending on many factors that include but are not limited to:

Disease progression of HCV is linear. Onset of acute hepatitis C is rarely recognized due to lack of symptoms; chronic HCV infection is also is generally a silent condition; and the course of the disease is often markedly protracted, spanning 20-40 years before the severe liver damages manifest. There is a variable rate of fibrosis progression with a median time from infection to cirrhosis of approximately 30 years (range 13-42 years). Independent factors associated with an increased rate of fibrosis progression include age at infection greater than 40 years, daily consumption of 50 g or more alcohol, and male sex.

In HCV associated compensated (stable) cirrhotics, five year survival is over 90% and 10 year survival 80%. A five year follow up showed that the risk of developing HCC was 7% (1.4%) and 18% decompensated. After decompensation, prognosis is poor with 50% survival at five years.

Natural history of HCV infection

Treatment

All patients with chronic HCV infection should be evaluated for treatment with peginterferon and ribavirin. The duration of therapy will be determined depending on HCV genotype. Patients with genotype 1 infection typically have sustained virologic response (SVR) rate of 40-55%, whereas those with genotype 2 or 3 have higher rates at 70-90%. Patients with genotype 1 or 4 require treatment for 48 weeks, whereas those with genotype 2 or 3 can receive 24 weeks of therapy.

Liver transplantation is the only effective treatment for liver failure but is greatly limited by the shortage of donor organs. Due to the shortage of donor livers and other organs, tissue engineering and regenerative medicine have emerged. Interferon alpha (IFN) is the drug of choice for the treatment of recurrent hepatitis C (HCV) in liver transplant recipients, but one of its potential adverse effects is acute and chronic rejection. The capability of the liver to fully regenerate after injury is a unique phenomenon which is essential for the maintenance of its important biological functions in the control of metabolism and detoxification. Genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Functions of growth factors, cytokines and their downstream signalling targets in liver regeneration are being studied in genetically modified mice.

Interferon and Ribavirin Treatment Side Effects (government website)

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Definitions of treatment responses

Rapid virologic response (RVR) Undetectable HCV RNA at week 4 of therapy
Early virologic response (EVR) At least 2-log reduction in HCV RNA by 12 weeks of therapy
End-of-treatment response No detectable HCV RNA at the end of therapy
Sustained virologic response (SVR) No detectable HCV RNA at the conclusion of treatment and 24 weeks after discontinuation of therapy
Breakthrough Reappearance of HCV RNA while still receiving therapy
Relapse Reappearance of HCV RNA after discontinuation of therapy
Nonresponder Failure to achieve undetectable HCV RNA after 24 weeks of therapy
Partial responder At least 2-log reduction in HCV RNA but never reaches undetectable HCV RNA

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Vaccination

In contrast to HBV, effective vaccination against the HCV is not available to date. Three factors contributed to this: (1) the high propensity of HCV to promote chronic persistent infections; (2) evidence that convalescent humans and chimpanzees could be readily reinfected following re-exposure and (3) the considerable genetic heterogeneity of this positive-stranded RNA virus.

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Diagnosis

The diagnosis of acute hepatitis C relies on the quantitative detection of HCV RNA, which may appear as early as 1-2 weeks after exposure, quickly followed by highly elevated ALT.

Qualitative and quantitative methods for detection of HCV RNA include reverse-transcriptase PCR, branched DNA assays and transcription-mediated amplification. Detection of HCV RNA by these methods without detectable antibodies suggests acute infection, especially when it is followed by seroconvesion.

The diagnosis after a suspected exposure is a special concern. The CDC recommends testing antibodies against HCV and measuring ALT concentrations as baseline, testing for HCV RNA by PCR at 4-6 weeks after exposure, and again for antibodies against HCV and ALT concentrations at 4-6 months.

Enzyme immunoassay for antibody to HCV is the initial serologic test for current and/or established HCV infection. HCV RNA levels also can be indicative of chronic infection. Most patients with chronic HCV will have levels of HCV RNA (viral load) between 100,000 (105) and 10,000,000 (107) copies/ml (or 50,000 - 5,000,000,000 IU/ml).

In June 2010, the U.S. Food and Drug Administration (FDA) approved the first rapid blood test for antibodies to HCV (OraQuick HCV Rapid Antibody Test; OraSure Technologies, Bethlehem, PA). It is approved for use in patients aged 15 years or older. The test is approved for screening persons who are considered at risk for HCV infection and works from a sample of venous blood, with readable results in about 20 minutes.

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HCV genome and proteins

HepC genome structure and proteins

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Life cycle

Key steps in the life cycle of HCV include entry into the host cell, uncoating of the viral genome, translation of viral proteins, viral genome replication, and the assembly and release of virions. All these events occur outside the nucleus of the host cell.

Entry

The HCV life cycle starts with viral attachment, entry, and fusion, which involve both the HCV structural proteins and the receptor molecules at the surface of target cells. Two HCV envelope glycoproteins, E1 and E2, are essential for viral entry and fusion. A few cell surface molecules, such as CD81, the human scavenger receptor class B type 1 (SR-B1), claudin-1, occludin, LDL receptor, and other putative receptor molecules have been proposed to mediate HCV binding or HCV binding and internalization.

Replication

After fusion of the viral and cellular membranes, viral nucleocapsid releases a single-stranded, positive-sense genomic RNA into the cell cytoplasm. This genome serves as a messenger RNA (mRNA) for synthesis of a large polyprotein (HCV polyprotein translation). It can also be a template for HCV RNA replication, or be packaged as a new genome in a progeny virus particle. At least two host cellular peptidases, i.e., host signal peptidase and signal peptide peptidase, are required for processing of the HCV structural proteins from the HCV polyprotein. A few viral enzymes, including the NS3-4A serine protease, are involved in the HCV polyprotein cleavage for generation of nonstructural proteins. This is followed by HCV RNA replication. The precise mechanism of HCV replication is largely unknown, but the process is thought to be semiconservative and asymmetric: the positive-strand genome RNA serves as a template for the synthesis of a negative-strand intermediate; the negative-strand RNA then serves as a template to produce multiple nascent genomes. NS5B RNA-dependent RNA polymerase (RdRp), a product of the polyprotein cleavage, is thought to catalyze HCV RNA replication.

Assembly and release

Viral particle formation is probably initiated by the interaction of the core protein with genomic RNA. The HCV envelope glycoproteins E1 and E2 associate with ER membranes through their transmembrane domains, which implies that virus assembly occurs in the ER. Structural proteins have been detected both in the ER and the Golgi apparatus, which suggests that both compartments are involved in later maturation steps. A distinctive property of the HCV E proteins in their position in the ER compartment indicates that viral nucleocapsids acquire their envelopes by budding through ER membranes, and in this case suggests that the virus may be exported via the constitutive secretory pathway.

Several studies have shown that maturation and release of HCV particles, that is the late stage of assembly, is tightly linked to the VLDL (very high density lipoprotein) pathway. Thus, HCV envelopment and maturation could take place in a specialized lipid-rich microdomain at the ER membrane, enriched for LDs and supporting synthesis of luminal LDs (luLDs), the precursors of VLDL. Cell fractionation experiments have shown that core protein accumulates in detergent-resistant lipid fractions containing high amounts of cholesterol and sphingolipids. In line with this observation, it was shown that these two lipids are enriched in HCV particles and play a crucial role regarding their infectivity. During assembly the nucleocapsid can be inserted within the core of luLDs. How the envelope glycoproteins are targeted to these assembly sites and incorporated into virions is unclear. It is still enigmatic how the apolipoproteins are incorporated into mature infectious particles. Mature HCV particles containing apoB, apoE and other apolipoproteins are transported along the VLDL secretory pathway. Virions thus have the overall structure of triglyceride-rich lipoproteins (TRLs) with a core of neutral lipids surrounded by a monolayer of phospholipids and stabilized by the apolipoproteins.

HCV infection is correlated well with alterations in body's lipid metabolism, in particular, lipid droplets (LD) accumulation in the liver (steatosis), which may accelerate the disease progression. HCV core proteins are preferentially associated with LDs and induce the enhancement of intracellular LDs, which is probably involved in the steatosis in HCV-infected patients. In addition, the core protein on LDs recruits the replication complexes to the LD-associated membranes via the core- NS5A interaction, leading to efficient infectious virus production. These strongly suggest that the link between LDs and the core protein is essential for both HCV pathogenesis and the virus life cycle. The unique membranous environment (membranous web) constructed around the core-associated LDs might build and coordinate a "HCV factory", the center of the viral replication and assembly. VLDL biogenesis and the secretion pathway are also greatly associated with this LD-dependent HCV production. Host factors involved in the LD-dependent virus formation pathway remain poorly understood. Biochemical studies focusing on LDs, LD-associated membranes, lipoproteins, and HCV virions in HCV-producing cells will help to identify these factors and to understand the molecular mechanism underlying the virus morphogenesis. The LD-dependent HCV production pathway may be an important component of future strategies for the prevention and treatment of HCV infection.

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Association between HCV and malignancies

Chronic HCV infection is a major risk factor for hepatocellular carcinoma (HCC) development and serological markers of HCV infection are found in up to 80% of patients with HCC in some areas of the world. HCV infection is estimated to increase the risk for HCC development up to 17-fold. Host, environmental and viral factors appear to play an important role in determining progression of chronic hepatitis C to liver cirrhosis and HCC. Some, but not all clinical studies, suggest that the risk of HCC development is associated with certain HCV genotypes, particularly genotype 1b. Apart from chronic HCV infection other risk factors for HCC development are among others HBV infection, obesity in men, diabetes mellitus, heavy alcohol use and hereditary hemochromatosis. Successful clearance of chronic HCV infection has been shown to reduce the overall liver-related mortality and HCC incidence, providing further evidence for a causal role of HCV in this cancer. Apart from HCC, HCV is also a well-established risk factor of lymphoproliferative syndromes such as type II mixed cryoglobulinemia and malignant lymphoma. Indeed, HCV infection increases the risk of B-cell non- Hodgkin lymphoma (B-NHL) 2- to 10-fold. This association is particularly striking in southern Europe but much less in northern Europe and North America, suggesting that differences in HCV prevalence in these geographic regions, in control populations and in methods of HCV detection may account for these findings. The mechanisms underlying HCV-related lymphoma development, including the contributing host and viral factors remain to be identified. Clinical data show a regression of lymphoma after successful treatment of HCV infection supporting the concept of HCV infection as a cause of lymphoma development in humans. HCV infection has also been linked to the development of intrahepatic cholangiocarcinoma (ICC). It remains unclear, however, whether this association is independent from the underlying liver disease/cirrhosis.

Prospective and retrospective cohort studies of patients with HCV infection have shown the role of the duration of chronic hepatitis in HCC development and the link between HCC development and liver cirrhosis. These studies demonstrated the sequential occurrence of advanced liver fibrosis and the development of HCC. The incidence of HCC development was estimated to be between 3 and 5%/year in patients with liver cirrhosis. In HCV-infected patients, host and environmental factors appear to be more important than viral factors in determining progression of the liver disease to cirrhosis and HCC. These factors include: older age at diagnosis (>55 years: 2- to 4-fold increased risk), duration of infection, male sex (2- to 3- fold increased risk), severity of liver disease at presentation, co-morbidities such as porphyria cutanea tarda, heavy alcohol intake, diabetes mellitus, steatosis, obesity and coinfections, especially with HBV. Slightly elevated serum bilirubin levels, decreased platelet counts and skin manifestations of liver disease, such as vascular spiders and/or palmar erythema correlate with the HCC risk.

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HCV and metabolic syndrome

Similar to non-alcoholic fatty liver disease (NAFLD), ER/oxidative stress, steatosis and insulin resistance (IR) are involved in the pathogenesis of chronic HCV infection, either as metabolic predisposition or directly induced by HCV. An increased prevalence of steatosis and IR has been observed in patients with HCV infection and has prognostic implications, as it is associated with faster progression to cirrhosis and HCC as well as with a poorer response to treatment. In patients infected with HCV genotypes 1 and 2, steatosis often develops in the context of a pre-existing diabetes, IR or increased body mass index. By comparison, in patients infected with HCV genotype 3, steatosis is directly induced by HCV, because it correlates with the viral load and reverses with response to antiviral treatment. HCV is thought to induce steatosis by interfering with lipid secretion and degradation and by increasing lipid synthesis. The HCV core protein, which localizes to the surface of lipid droplets and mediates viral assembly in close association with the cellular fatty acid metabolism, as well as some HCV non-structural proteins, have been shown to interfere with VLDL secretion. HCV infection also upregulates lipid synthesis, inhibits fatty acid oxidation and increases release of fatty acids from adipocytes. Overall the effects of HCV proteins on lipid synthesis, secretion and oxidation seem to be most pronounced in HCV genotype 3 infection, but also occur in patients infected with other genotypes. Besides changes in the lipid metabolism, HCV core and several non-structural proteins, induce systemic oxidative stress and related signaling by various mechanisms. With respect to IR, all HCV genotypes have been shown to interfere with glucose homeostasis, often at early stages in HCV infection.

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References

  1. Hepatitis C - free articles in PubMed
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    Schematic diagram of the HCV genome

    Schematic diagram of the HCV genome. The positive-stranded genome RNA of HCV is of approximately 9.6 Kb and is flanked by the 5'- and 3'-untranslated regions (UTR). The coding sequence of HCV viral RNA encodes a single polypeptide through internal ribosome entry site (IRES)-mediated translation. The nascent translated polypeptide is subsequently processed by a combination of cellular and viral proteases to mature into structural proteins (core, E1, E2, and p7) and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). Core, E1, and E2 constitute the components of viral particle (red asterisks) whereas NS4A and NS5B specifically function in the replication of viral RNA. NS2 and p7 are involved in the assembly of viral particles. NS3, NS4B, and NS5A have its dual role in both viral replication and assembly.

    Schematic representation of the HCV viral life cycle

    Schematic representation of the HCV viral life cycle. The viral particles associated with lipoproteins enter into host cells via (co)receptor binding and clathrin-mediated endocytosis. The known entry (co)receptors, tetraspanin CD81, the scavenger receptor class B member I (SR-BI), Claudin 1 (CLDN1), Occludin (OCLN), glycosaminoglycans (GAG), the low-density lipoprotein receptor (LDLR), epidermal growth factor receptor (EGFR), ephrin receptor A2 (EphA2), and Niemann-Pick C1-like L1 (NPC1L1) are indicated. After uncoating process, the positive-stranded viral RNA is released, translated, and processed into different viral proteins. The NS viral proteins mediate the replication of positive-stranded viral RNA within a membranous structure, called membranous web. The infectious viral particles containing the newly-synthesized viral RNA and structural proteins are assembled and egressed via the secretory pathway.

    Schematic representation of the HCV viral life cycle

    Pathogenesis of HCV-associated liver diseases. Approximately 3% of the population has been infected with HCV worldwide. In the majority (about 50-80%) of infected individuals it becomes a persistent-infection and the chronic-infected hepatocytes in liver progressively develop into liver steatosis, and liver cirrhosis. Ultimately, the chronic infection leads to hepatocellular carcinoma formation in nearly 3-5% of viral-infected patients.

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    The stellate cell: a key cell implicated in fibrogenesis.

    The stellate cell: a key cell implicated in fibrogenesis. Hepatic stellate cells (HSCs) exist in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule, and store vitamin A as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of vitamin A homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. In a normal state, HSCs appear as quiescent vitamin A-storing cells. When activated via several stimuli (infection, alcohol, cytokines, etc.) they acquire a proliferative myofibroblast phenotype. In pathological conditions such as chronic hepatitis C, HSCs lose vitamin A and synthesise a large amount of extracellular matrix components including collagen, proteoglycan and adhesive glycoproteins. Kupffer cells, the resident liver macrophages, remove material from the portal circulation. Kupffer cells may act both as effector cells in the destruction of hepatocytes by producing harmful soluble mediators and as antigen-presenting cells during viral infections of the liver. Moreover, they may represent a significant source of chemoattractant molecules for cytotoxic CD8 and regulatory T cells. Their role in fibrosis is well established as they are one of the main sources of transforming growth factor β1 production, which leads to the transformation of HSCs into myofibroblasts.

    Scoring system for chronic hepatitis C (the Metavir Score System).

    Scoring system for chronic hepatitis C (the Metavir Score System). Liver biopsy remains the gold standard to assess fibrosis. According to the Metavir Score System, fibrosis is scored as F0 (absent), F1 (portal fibrosis), F2 (portal fibrosis with few septa), F3 (septal fibrosis) and F4 (cirrhosis). In addition, necroinflammation activity (A) is graded as A0 (absent), A1 (mild), A2 (moderate) or A3 (severe).

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    The stellate cell: a key cell implicated in fibrogenesis.

    Working model of HCV assembly. Viral assembly is triggered by the encounter of three modules: core, E1E2p7NS2 complex and the replication complex (RC). The assembly site is supposed to be in the membranous microenvironment of the lipid droplet (LD) and the endoplasmic reticulum (ER). The driving force of viral budding potentially comes from three directions: pushing force of the nascent nucleocaspsid, the pulling force of envelope proteins which might stabilize the viral surface architecture by intermolecular disulfide bridges and the force of the nascent luminal LD (luLD) between the ER leaflets. The result is a hybrid lipoviroparticle, which acquires ApoE presumably by its lipid component and in primary hepatocytes the lipoprotein moiety may mature into a VLDL-like structure (adapted from [46]). MTP stands for microsomal triglyceride transfer protein that is involved in the VLDL pathway. sER/mw is for smooth ER/ membranous web where the HCV replication is believed to take place.

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