Hepatitis C databases, principles and utility to researchers

Abstract

Part of the effort to develop hepatitis C-specific drugs and vaccines is the study of genetic variability of all publicly available HCV sequences. Three HCV databases are currently available to aid this effort and to provide additional insight into the basic biology, immunology, and evolution of the virus. The Japanese HCV database (http:// s2as02.genes.nig.ac.jp) gives access to a genomic mapping of sequences as well as their phylogenetic relationships. The European HCV database (http://euhcvdb.ibcp.fr) offers access to a computer-annotated set of sequences and molecular models of HCV proteins and focuses on protein sequence, structure and function analysis. T he hepatitis C virus (HCV) has infected approximately 170 million people worldwide. HCV infection is cleared in about 25% of cases, 1,2 and in the rest results in chronic infection. Chronic HCV infection can lead to cirrhosis and liver cancer, and is the leading cause of liver transplantation in the United States. A recent Canadian study 3 estimated that lifetime HCV-associated mortality is around 1 in 8; a much larger number (an estimated 1 in 4) will develop cirrhosis of the liver. Most likely this number will be higher in less developed countries. With 170 million people infected worldwide, this means 20 million HCVrelated deaths in the next few decades.HCV is a positive-sense RNA virus with a genome of Ϸ10 kb, which encodes a single polyprotein of Ϸ3000 amino acids (aa) that is cleaved into three structural proteins (core, Envelope E1 and E2), the p7 protein whose function has not been determined, and six non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B). It has been classified as a hepacivirus, in of the Flaviviridae family, which also includes flaviviruses (West Nile, Japanese encephalitis and yellow fever viruses) and pestiviruses (bovin viral diarrhea and hog cholera virus). HCV shares some structural features with these viruses. However, the genetic distance between HCV and other flaviviruses is large enough that HCV cannot be meaningfully aligned to its flavivirus "relatives" over its entire genome 4 (also see http://hcv.lanl.gov/content/hcv-db/GET_ALIGNMENTS/ flavi-align.html), and it also shares structural features with the pestivirus family.HCV is subdivided into six genotypes and about 80 subtypes on the basis of nucleotide sequence identity. 5 In addition to genotypes, HCV exists within its hosts as a pool of genetically distinct but closely related variants referred to as quasispecies. 6 While there is limited knowledge about the immunogenicity of HCV, it is widely expected that both the generation of escape and resistance mutations and the high variability itself will create formidable problems for drug and vaccine design. 7 This paper discusses three HCV databases available worldwide, in order of seniority: the Japanese HCV map and phylogeny database, the European HCV sequence and molecular models database and the Los Alamos HCV sequence and immunology databases. We will first describe the three databases, highlighting comm...

Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus

“…Clearly, these alterations in the 412-423 epitope do not abrogate HCV1 or 95-2 binding or neutralization. To further confirm that this epitope is refractory to mutation, we performed an extensive analysis of the amino acid sequences of residues 412 to 423 in E2 proteins found in the NIH HCV database (19). Of the sequences in the HCV database, 56% have an amino acid sequence at residues 412 to 423 that is identical to that of the H77-derived 1a glycoprotein that was used in this study.…”

Disulfide Bonds in Hepatitis C Virus Glycoprotein E1 Control the Assembly and Entry Functions of E2 Glycoprotein

“…Genotype and accession number (in the Genotypes column) and strain are indicated for each sequence. Amino acids are numbered with respect to the polyprotein of HCV strain H77, used as a reference (top row) (42). The positions of conserved cysteine residues are indicated in magenta (top row).…”

Identification of Alpha Interferon-Induced Envelope Mutations of Hepatitis C Virus In Vitro Associated with Increased Viral Fitness and Interferon Resistance

“…Cloning plans were developed using Vector NTI (Invitrogen). HCV sequences and number tools for determination of H77 reference numbers were from the European and Los Alamos HCV databases (35)(36)(37). Ready-made alignments of genotype 1a and 3a HCV sequences were from the Los Alamos 2008 web alignment.…”