Assays for RNA synthesis and replication by the hepatitis C virus

doi:10.1007/s11515-012-1188-0

Front Biol

2012, Vol. 7

Issue (3) : 233-245 https://doi.org/10.1007/s11515-012-1188-0

REVIEW

Assays for RNA synthesis and replication by the hepatitis C virus

C. Cheng KAO¹(

), Baochang FAN¹, Sreedhar CHINNASWAMY², Hui CAI¹, C.T. RANJITH-KUMAR¹, Jerome DEVAL³

1. Department of Molecular & Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA; 2. National Institute of Biomedical Genomics (NIBMG), NSS, Kalyani, WB-741251, India; 3. Alios BioPharma, Inc., South San Francisco, CA 94080, USA

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Abstract

At least six major genotypes of Hepatitis C virus (HCV) cause liver diseases worldwide. The efficacy rates with current standard of care are about 50% against genotype 1, the most prevalent strain in the United States, Europe and Japan. Therefore more effective pan-genotypic therapies are needed. HCV RNA replication provides a number of validated targets for virus-specific and potentially pan-genotypic inhibitors. In vitro assays capturing the different steps of RNA synthesis are needed not only to identify new inhibitors, but also to examine their mechanisms of action. This review attempts to provide a comprehensive summary of the biochemical, cell-based and animal model systems to assess HCV polymerase activity and HCV RNA replication that should be useful for both basic research and applied studies.

Keywords assay RNA synthesis and replication hepatitis C virus

Corresponding Author(s): KAO C. Cheng,Email:ckao@indiana.edu

Issue Date: 01 June 2012

Cite this article:

Sreedhar CHINNASWAMY,Hui CAI,C. Cheng KAO, et al. Assays for RNA synthesis and replication by the hepatitis C virus[J]. Front Biol, 2012, 7(3): 233-245.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-1188-0
https://academic.hep.com.cn/fib/EN/Y2012/V7/I3/233

Fig.1 The organization of the HCV genome and the processing and functions of the ten mature HCV proteins. The HCV genome with the flanking non-translated regions (NTR) and the HCV-encoded structural and nonstructural proteins are shown in the upper diagram. The black box denotes the location of the internal ribosome entry sequence that facilitated cap-independent translation of the HCV polyprotein. Processing of the polyproteins by cellular proteases are denoted by triangles. The sites processed by the HCV-encodedNS2 and NS3 are shown with white and black arrows, respectively. A summary of the functions of the proteins is shown below the proteins.

Fig.2 A schematic for the infection process by HCV. The major steps in HCV infection are depicted and labeled. The nucleus is depicted with a blue oval and the endoplasmic reticulum shown with grey lines. The ribosome is translating the (+)-strand HCV genomic RNA (black line) is depicted by the two small grey ovals. Newly synthesized (-)-strand RNA is in red. RNA synthesis takes place in association with the membranous web.

Fig.3 A model for de novo initiated RNA synthesis bythe NS5B protein and the locations of the four pockets targeted by nonnucleoside inhibitors. ) A model for de novo initiated RNA synthesis by the HCV NS5B protein. The three subdomains of the polymerase are shown in different shades of grey while the active site residues are shown as green asterisks. The blue line represents the Δ1 loop, which regulates a major conformational change needed for the transition from initiation to elongative RNA synthesis. The thick red line denotes the template RNA. The first two schematics (counted from the left) denotes the binding of either the initiation nucleotide, GTP, or binding of the template RNA. The third schematic denotes the formation of a ternary complex. The last schematic shows the conformational change that takes place upon the synthesis of the nascent RNA. This conformational change is necessitated by the steric constrains of the closed template channel. ) A space fill model of the 1b HCV polymerase (PDB ID: 1QUV). Key features illustrated are the Δ1 loop (in blue ribbon structure), the four allosteric sites that can bind nonnucleoside inhibitors, and the divalent metal-binding active site (gold). HCV 1b genotype NS5B (PDB ID: 1QUV) was used for the model. The four drug binding pockets were as described by Pauwels et al. (). The models were generated using the program Chimera from UCSF.

Fig.4 Schematics of the cell-based subgenomic replicons developed to facilite studies of HCV replication. (A) A bi-cistronic HCV subgenomic replicon originally designed by Lohmann et al. (). This replicon is composed of the HCV 5′NTR, selectable marker gene Neo, IRES from EMCV, HCV nonstructural genes NS3 to NS5B and HCV 3′NTR. (B) A reporter replicon suitable for transient transfection assay. (C) A selectable reporter replicon, in which reporter gene and selectable marker gene (Neo) were joined by a cleavable ubiquitin (Ubi) sequences in the first cistron. (D) Structure of mono-cistronic reporter replicon. In this construct, the reporter gene is fused in frame to the HCV NS3-NS5B by ubiquitin, the fusion polyprotein is translated by the HCV IRES. (E). Diagram for the 5BR assay, an indirect assay that amplifies signals for RNA synthesis by the HCV polymerase through RIG-I-dependent activation of reporter production ().

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