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Advancement in the development of models for hepatitis C research.

Carcamo WC, Nguyen CQ - J. Biomed. Biotechnol. (2012)

Bottom Line: Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment.Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans.This review focuses on experimental models that have been developed to date and their findings related to HCV.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA.

ABSTRACT
Hepatitis C virus (HCV) is a pandemic disease affecting an estimated 180 million individuals worldwide and infecting each year another ~3-4 million people making HCV a global public health issue. HCV is the main cause for chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In the United States, HCV-related chronic liver disease is a leading cause of liver transplantation. Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment. Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans. For decades, the chimpanzee model has been the only and instrumental primate for studying HCV infection; however, availability, economic, and ethical issues make the chimpanzee an unsuitable animal model today. Thus, significant research has been devoted to explore different models that are suitable in studying the biology of the virus and application in the clinical research for developing efficient and tolerable treatments for patients. This review focuses on experimental models that have been developed to date and their findings related to HCV.

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Related in: MedlinePlus

HCV genome and polyprotein cleavage products. A schematic representation of the HCV genome indicating the structural and nonstructural regions, including the 5′ and 3′ NTRs. The polyprotein cleavage products are drawn within. The cleavage site and the corresponding protease are indicated (arrows).
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fig1: HCV genome and polyprotein cleavage products. A schematic representation of the HCV genome indicating the structural and nonstructural regions, including the 5′ and 3′ NTRs. The polyprotein cleavage products are drawn within. The cleavage site and the corresponding protease are indicated (arrows).

Mentions: HCV was originally referred to as non-A non-B Hepatitis (NANB). In 1989, a major breakthrough in HCV research was discovered in which the complete sequence of the viral genome was identified and cloned by Choo and collaborators [13]. HCV is the only member of the Hepacivirus genus that belongs to the Flaviviridae family [14, 15]. Structural analysis of the virus revealed that the genetic material is surrounded by a protective nucleocapside, composed mainly of the protein core (C), and further protected by a lipid envelope [16]. The lipid envelope contains two major glycoproteins, envelope protein 1 (E1) and E2, that are embedded in the envelope [17]. The genome consists of a single open-reading frame (ORF), that is, ~9,600 nucleotides long, which is made into a single polyprotein (3,010 or 3,033 amino acids) product (Figure 1) [18, 19]. The HCV genome is flanked by two nontranslated regions (NTRs), which are essential in the replication and synthesis of viral proteins. Viral and cellular proteases mediate the processing of the polyprotein into structural (core, E1, E2, and p7) and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) as illustrated in Figure 1 [20–22]. The HCV life cycle is entirely cytoplasmic and replication occurs mainly in hepatocytes, but the virus may also replicate in peripheral blood mononuclear cells (PBMCs). The virus enters the host cells through a complex interaction between virions and cell surface molecules CD81, LDL receptor, scavenger receptor class B type 1 (SR-B1), Claudin-1, and Occludin [23–26]. Recent studies by Ray et al. and Sainz et al. have identified Niemann-Pick C1-like 1 (NPC1L1) cholesterol absorption receptor as a new HCV entry factor [27, 28]. Once inside the cell, the virus takes over the intracellular machinery to replicate [29]. Due to its high-mutation rate caused by the virus' RNA-dependent RNA polymerase (NS5B), which lacks 3′-5′ exonuclease activity [30], HCV is considered a quasispecies composed of 6 genotypes with several subtypes [12]. The eleven genotypes have differences in geographic distribution, disease progression, and response to therapy. Genotypes 1, 2, and 3 are distributed worldwide, with genotypes 1a and 1b accounting for 60% of global infections. In the United States, genotypes 1a and 2b are more commonly encountered.


Advancement in the development of models for hepatitis C research.

Carcamo WC, Nguyen CQ - J. Biomed. Biotechnol. (2012)

HCV genome and polyprotein cleavage products. A schematic representation of the HCV genome indicating the structural and nonstructural regions, including the 5′ and 3′ NTRs. The polyprotein cleavage products are drawn within. The cleavage site and the corresponding protease are indicated (arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369559&req=5

fig1: HCV genome and polyprotein cleavage products. A schematic representation of the HCV genome indicating the structural and nonstructural regions, including the 5′ and 3′ NTRs. The polyprotein cleavage products are drawn within. The cleavage site and the corresponding protease are indicated (arrows).
Mentions: HCV was originally referred to as non-A non-B Hepatitis (NANB). In 1989, a major breakthrough in HCV research was discovered in which the complete sequence of the viral genome was identified and cloned by Choo and collaborators [13]. HCV is the only member of the Hepacivirus genus that belongs to the Flaviviridae family [14, 15]. Structural analysis of the virus revealed that the genetic material is surrounded by a protective nucleocapside, composed mainly of the protein core (C), and further protected by a lipid envelope [16]. The lipid envelope contains two major glycoproteins, envelope protein 1 (E1) and E2, that are embedded in the envelope [17]. The genome consists of a single open-reading frame (ORF), that is, ~9,600 nucleotides long, which is made into a single polyprotein (3,010 or 3,033 amino acids) product (Figure 1) [18, 19]. The HCV genome is flanked by two nontranslated regions (NTRs), which are essential in the replication and synthesis of viral proteins. Viral and cellular proteases mediate the processing of the polyprotein into structural (core, E1, E2, and p7) and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) as illustrated in Figure 1 [20–22]. The HCV life cycle is entirely cytoplasmic and replication occurs mainly in hepatocytes, but the virus may also replicate in peripheral blood mononuclear cells (PBMCs). The virus enters the host cells through a complex interaction between virions and cell surface molecules CD81, LDL receptor, scavenger receptor class B type 1 (SR-B1), Claudin-1, and Occludin [23–26]. Recent studies by Ray et al. and Sainz et al. have identified Niemann-Pick C1-like 1 (NPC1L1) cholesterol absorption receptor as a new HCV entry factor [27, 28]. Once inside the cell, the virus takes over the intracellular machinery to replicate [29]. Due to its high-mutation rate caused by the virus' RNA-dependent RNA polymerase (NS5B), which lacks 3′-5′ exonuclease activity [30], HCV is considered a quasispecies composed of 6 genotypes with several subtypes [12]. The eleven genotypes have differences in geographic distribution, disease progression, and response to therapy. Genotypes 1, 2, and 3 are distributed worldwide, with genotypes 1a and 1b accounting for 60% of global infections. In the United States, genotypes 1a and 2b are more commonly encountered.

Bottom Line: Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment.Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans.This review focuses on experimental models that have been developed to date and their findings related to HCV.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA.

ABSTRACT
Hepatitis C virus (HCV) is a pandemic disease affecting an estimated 180 million individuals worldwide and infecting each year another ~3-4 million people making HCV a global public health issue. HCV is the main cause for chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In the United States, HCV-related chronic liver disease is a leading cause of liver transplantation. Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment. Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans. For decades, the chimpanzee model has been the only and instrumental primate for studying HCV infection; however, availability, economic, and ethical issues make the chimpanzee an unsuitable animal model today. Thus, significant research has been devoted to explore different models that are suitable in studying the biology of the virus and application in the clinical research for developing efficient and tolerable treatments for patients. This review focuses on experimental models that have been developed to date and their findings related to HCV.

Show MeSH
Related in: MedlinePlus