Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees

Forns, Xavier; Thimme, Robert; Govindarajan, Sugantha; Emerson, Suzanne U.; Purcell, Robert H.; Chisari, Francis V.; Bukh, Jens

doi:10.1073/pnas.230453597

Cited by 135 publications

(124 citation statements)

References 49 publications

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“…These infectious clones were used to show that all viral enzyme activities, the p7 gene and the correct genomic 3፱ end are necessary for HCV replication in vivo [54][55][56] . In contrast, the hypervariable N-terminal region of E2 is dispensible 57 . Essentially clonal infections could be initiated from transcribed RNA, providing a well-defined genetic starting point to study virus evolution and immune responses to infection 58 .…”

Section: Mechanisms Of Hcv Rna Replicationmentioning

confidence: 97%

“…As this overlaps with the IRES, there is considerable interest in understanding how this region might modulate translation and replication, which are unlikely to occur simultaneously on the same RNA template. The 3፱ NCR has been found to contain a nonessential variable region, a poly-U/UC tract that must be more than 26 nucleotides long, followed by a highly conserved and essential 3፱X domain 55,57,76 . Recently a conserved stem-loop structure within the NS5B coding region, 5BSL3.2, was found to be required for RNA replication 78 .…”

Section: Mechanisms Of Hcv Rna Replicationmentioning

confidence: 99%

See 1 more Smart Citation

Unravelling hepatitis C virus replication from genome to function

Lindenbach

Rice

2005

Nature

751

561

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Since the discovery of the hepatitis C virus over 15 years ago, scientists have raced to develop diagnostics, study the virus and find new therapies. Yet virtually every attempt to dissect this pathogen has met with roadblocks that impeded progress. Its replication was restricted to humans or experimentally infected chimpanzees, and efficient growth of the virus in cell culture failed until very recently. Nevertheless hard-fought progress has been made and the first wave of antiviral drugs is entering clinical trials.virus life cycle: first, as a messenger RNA (mRNA) for translation of the viral proteins; second as a template for RNA replication; and third, as a nascent genome packaged within new virus particles. Virions presumably form by budding into the endoplasmic reticulum (ER) and leave the cell through the secretory pathway.Researchers have followed each aspect of the virus life cycle in turn. Just as infection starts from an HCV genome entering the cytoplasm and progressing through translation, replication and particle production, our understanding has progressed from having a genome sequence to understanding translation and the viral gene products, characterizing RNA replication, and establishing systems to characterize virus particles and infectivity. In this review, we summarize the current understanding of HCV replication with special emphasis on recent developments. As space is limited, we cannot be comprehensive; readers may wish to consult other reviews for detail and breadth 5,13,14. Initial studies: HCV translation and polyprotein processingThe identification of HCV yielded a partial viral genome sequence 5 . Research in the early 1990s focused on dissecting HCV gene expression and characterizing the gene products. Much has been learned about the biochemistry of three key enzymes, and structural information is now available at the atomic level for roughly half of the proteincoding region.Translation of the HCV genome, which lacks a 5፱ cap, depends on an internal ribosome entry site (IRES) within the 5፱-noncoding region (NCR). The HCV IRES binds 40S ribosomal subunits directly and avidly, bypassing the need for pre-initiation factors, and inducing an mRNA-bound conformation in the 40S subunit 15 . The IRES-40S complex then recruits eukaryotic initiation factor (eIF) 3 and the ternary complex of Met-tRNA-eIF2-GTP to form a non-canonical 48S intermediate, before a kinetically slow transition to the translationally active 80S complex 16,17 .Once initiated, translation of the HCV genome produces a large polyprotein that is proteolytically cleaved to produce 10 viral proteins (Fig. 2a). The amino-terminal one-third of the polyprotein encodes the virion structural proteins: the highly basic core (C) protein, and glycoproteins E1 and E2. After the structural region comes a small integral membrane protein, p7, which seems to function as an ion channel 18,19 . The remainder of the genome encodes the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, which coordinate the intracellular process...

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Section: Mechanisms Of Hcv Rna Replicationmentioning

confidence: 97%

Section: Mechanisms Of Hcv Rna Replicationmentioning

confidence: 99%

Unravelling hepatitis C virus replication from genome to function

Lindenbach

Rice

2005

Nature

751

561

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“…Remarkably, the E2 hypervariable region (HVR1) could be deleted without abrogating infectivity, although the mutant virus replicated poorly and compensating changes in E1 and E2 were selected upon passaging. 15 On the vaccine front, challenge of animals with resolved HCV infection using homologous or heterologous virus has provided evidence for protective immunity. This is an important proof of principle for vaccine development.…”

Section: Animal Models and Cell Culture Systemsmentioning

confidence: 99%

“…With this in mind, the AASLD has launched an annual single topic conference devoted exclusively to viral hepatitis with the intention of bringing together researchers in viral hepatitis to foster progress in this important area. The first of these conferences, held June [15][16] 2001 in Chicago, IL, focused on new, evolving, and future approaches to therapy of hepatitis C.…”

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confidence: 99%

New therapeutic strategies for hepatitis C

2002

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V iral hepatitis is the single most important cause of liver disease in the United States and worldwide. With this in mind, the AASLD has launched an annual single topic conference devoted exclusively to viral hepatitis with the intention of bringing together researchers in viral hepatitis to foster progress in this important area. The first of these conferences, held June [15][16] 2001 in Chicago, IL, focused on new, evolving, and future approaches to therapy of hepatitis C.Dr. Eugene Schiff (University of Miami) reviewed the history and impact of hepatitis C. It appears that the hepatitis C virus (HCV) emerged in the U.S. population beginning in the 1960s, related to blood transfusion and injection drug use, although the extent of the problem was only apparent after 1990 when reliable blood tests first became available for hepatitis C. 1 Studies of the natural history have been somewhat contradictory but indicate that over the first 20 years of chronic HCV infection, 20% of chronically infected patients will develop cirrhosis, and many of those will progress to hepatocellular carcinoma. 2 HCV-associated end-stage liver disease is now recognized as a leading indication for liver transplantation in the United States and the developed western world. 3 VirologyDr. Charles Rice (The Rockefeller University) described the virology of HCV; it has an RNA genome about 10,000 nucleotides in length. 4 A hallmark of this RNA is the presence of a long open reading frame (ORF) that encodes a polyprotein that is processed into at least 10 discrete polypeptides (Fig. 1). Translation initiation is mediated by the internal ribosome entry site (IRES). Progress made in understanding HCV IRES structure and function was reviewed by Dr. Stanley Lemon (University of Texas at Galveston). The HCV IRES resides within the 5Ј nontranslated region between nucleotides 44 and 342. Key structural features include two large stem-loops and a pseudoknot that involves sequences near the initiator codon. These structures have been deduced from thermodynamic modelling, phylogenetic analysis, chemical and enzymatic structure probing, X-ray crystallography, and nuclear magnetic resonance. The IRES forms a binary complex with the 40S ribosomal subunit in the absence of other translation initiation factors (unlike other viruses). 5 This high-affinity complex results in a conformational change in the 40S subunit and binding of eukaryotic initiation factor 3. Via this process, the AUG initiator codon of the viral RNA is positioned near the ribosome decoding site. A specific sequence is not then required to initiate translation, but a stem loop must "melt" to allow this process to proceed. This complex viral RNA element could thus be a rich target for compounds that inhibit translation.Processing of the polyprotein is mediated by the cellular enzyme, host signal peptidase, and two viral proteases, the NS2-3 autoprotease and the NS3-4A serine protease. This results in the production of the core or capsid protein (C), two envelope glycoproteins (E1 and E2),...

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“…11 Despite a strong amino acid sequence variability, the chemicophysical properties and the conformation of HVR1 have been shown to be well conserved, in agreement with a potential role in virus attachment. 12 However, it has been reported that an HCV clone lacking HVR1 was still infectious in chimpanzee, 13 indicating that HVR1 is not essential for infection in this species. In the hypothesis that SR-BI is a receptor for HCV, these data can only be explained by the existence of an alternative receptor.…”

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confidence: 99%

Another putative receptor for hepatitis C virus

Beeck

Dubuisson

2003

Hepatology

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We discovered that the hepatitis C virus (HCV) envelope glycoprotein E2 binds to human hepatoma cell lines independently of the previously proposed HCV receptor CD81. Comparative binding studies using recombinant E2 from the most prevalent 1a and 1b genotypes revealed that E2 recognition by hepatoma cells is independent from the viral isolate, while E2-CD81 interaction is isolate specific. Binding of soluble E2 to human hepatoma cells was impaired by deletion of the hypervariable region 1 (HVR1), but the wild-type phenotype was recovered by introducing a compensatory mutation reported previously to rescue infectivity of an HVR1-deleted HCV infectious clone. We have identified the receptor responsible for E2 binding to human hepatic cells as the human scavenger receptor class B type I (SR-BI). E2-SR-BI interaction is very selective since neither mouse SR-BI nor the closely related human scavenger receptor CD36, were able to bind E2. Finally, E2 recognition by SR-BI was competed out in an isolatespecific manner both on the hepatoma cell line and on the human SR-BI-transfected cell line by an anti-HVR1 monoclonal antibody. CommentsInfection of cells by viruses begins with the attachment of the virion to the surface of the host cell. Attachment is mediated by the binding of a protein present at the surface of the native virion to a molecule on the cell surface acting as a virus receptor. In addition to primary binding receptors, some viruses also interact with secondary receptors (coreceptors) that bind either to native virions or instead to altered forms of virions that are produced as a result of the primary binding step. Virus receptors and coreceptors are potentially any normal component associated with the host cell membrane. Because of their critical involvement in the early steps of infection, viral receptors and coreceptors are major determinants of viral tropism. However, their expression may not necessarily be the sole determinant for viral infection.The envelope glycoprotein complex E1-E2 is the viral component that is supposed to be present at the surface of hepatitis C virus (HCV) particles, 1 and it is therefore the obvious ligand candidate for cellular receptors. Alternatively, because of the physical association of HCV with low-or very low-density lipoproteins (LDL or VLDL) in serum, the LDL receptor has been proposed as a candidate receptor for HCV. 2,3 The LDL receptor has been reported to mediate HCV internalization via binding to virionassociated LDL particles, 2 but there is no available experimental data indicating that such interactions lead to a productive infection.In the absence of a suitable cell culture system for HCV, an alternative approach to search for candidate receptors has been to use truncated soluble forms of HCV glycoproteins for binding studies to human cells. 4 By using a soluble form of E2 as a probe, CD81 has been identified as another putative receptor for HCV, 5 and, by a very similar approach, Scarselli et al. have identified a third candidate receptor for HCV. Th...

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Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees

Cited by 135 publications

References 49 publications

Unravelling hepatitis C virus replication from genome to function

Unravelling hepatitis C virus replication from genome to function

New therapeutic strategies for hepatitis C

Another putative receptor for hepatitis C virus

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