The nucleotide sequence of the Japanese type of hepatitis C virus (HCV-J) genome, consisting of 9413 nucleotides, was determined by analyses of cDNA clones from plasma specimens from Japanese patients with chronic hepatitis. HCV-J genome contains a long open reading frame that can encode a sequence of 3010 amino acid residues. Comparison ofHCV-J with the American isolate of HCV showed 22.6% difference in nucleotide sequence and 15.1% difference in amino acid sequence. Thus HCV-J and the American isolate of HCV are probably different subtypes of HCV. The relationship of HCV-J with other animal RNA virus families and the putative organization of the HCV-J genome are discussed.
Processing of the putative structural proteins of hepatitis C virus was examined by using an in vitro expression system. An RNA transcript for cell-free translation was prepared from a cDNA construct that encompasses the region encoding the 980 amino-terminal residues of the viral polyprotein precursor. Processing of the in vitro translation product proceeded cotranslationally in the presence of microsomal membranes and generated four major membrane-associated products. Two of these four major products, named gp35 and gp7O, were shown to be transported into microsomes and heavily glycosylated, suggesting that the processing events are partly mediated by the signal peptidase of the endoplasmic reticulum. The other two products, p19 and p21, were probably associated with the outer surface of the microsomal membrane. Analysis of processed proteins translated from a series of truncated forms of the cDNA construct as well as determination of amino-terminal amino acid sequences of gp35 and gp7O indicated that these four products are arranged from the amino-terminal end of the polyprotein precursor in the order: NH-p22-gp35-gp7O-pl9. Both gp35 and gp7O could be candidates of initially processed forms of envelope proteins of the hepatitis C virus.Hepatitis C virus (HCV) is considered to be a causative agent of post-transfusion non-A, non-B hepatitis (1, 2). The enveloped virions consist of unknown species of structural proteins encoded by positive-stranded RNA genomes. This virus is probably related to pestiviruses and to flaviviruses judging from the similarities of the deduced amino acid sequences of the putative viral proteins (refs. 3 and 4 and unpublished results). Our recent study showed that genomic RNA ofHCV from Japanese patients with non-A, non-B hepatitis is more than 9413 nucleotides long and includes a single open reading frame (ORF) encoding a precursor polyprotein of 3010 amino acids (4). This precursor polyprotein has many basic amino acid residues clustered in its 120 amino-terminal residues deduced from the sequence of the ORF, as in the aminoterminal regions of nucleocapsid (C) proteins of flaviviruses (4,5). It also has 15 potential aspargine-linked glycosylation (N-glycosylation) sites clustered in the region of amino acid residues 196-645 like those found in putative envelope (E) glycoproteins of pestiviruses (4, 6). These data suggest that the genetic organization of HCV is almost identical to those of pestiviruses or flaviviruses and that the 5' portion of the genome encodes viral structural proteins.The gene order in the genome of flaviviruses has been determined to be C-premembrane (preM)-
A clinical isolate of Serratia marcescens (TN9106) produced a metallo 13-lactamase (IMP-1) which conferred resistance to imipenem and broad-spectrum 13-lactams. The consensus amino acid residues, His-95, His-97, Cys-176, and His-215, which form putative zinc ligands, were conserved in the deduced amino acid sequence of IMP-1. By determination of the amino acid sequence at the N terminus of purified mature IMP-1, 18 amino acid residues were found to be processed from the N terminus of the premature enzyme as a signal peptide. These results clearly show that IMP-1 is an enterobacterial metallo 13-lactamase, of which the primary structure has been completely determined, that confers resistance to carbapenems and other broad-spectrum 13-lactams.Many extended-spectrum 13-lactamases conferring high levels of resistance to broad-spectrum P-lactam antibiotics have been found worldwide with the increasing use of newly developed broad-spectrum P-lactam antibiotics (10, 11).They are mostly R plasmid-mediated TEM-or SHV-related class A enzymes (4,12,18,22,29,32). However, plasmidmediated AmpC-type ,-lactamases that belong to class C have recently been reported (9, 21). These plasmid-mediated extended-spectrum ,B-lactamases have a serine residue at the active center of the enzyme, and they effectively hydrolyze broad-spectrum ,-lactams, except carbapenems. Although it was reported by genetic analyses that bacteria belonging to the family Enterobacteriaceae, except Klebsiella spp. (1, 2) and Pseudomonas spp., have chromosomally encoded inducible AmpC 3-lactamases (8,14,16,20,26,34) times show resistance to imipenem and broad-spectrum P-lactams (7,17,37). The imipenem resistances of these bacteria are mainly due to the production of metallo 3-lactamases that belong to class B. The class B enzymes require zinc ions for enzyme activity and demonstrate a primary structure quite different from those of the class A and class C enzymes belonging to the group of serine P-lactamases.Recently, several strains of Serratia marcescens were reported to show resistance to carbapenems as well (35). In this study, we clearly show that a clinically isolated strain of S. marcescens (TN9106) showing resistance to imipenem has a chromosomally encoded metallo 3-lactamase gene.
Innate cellular antiviral defenses are likely to influence the outcome of infections by many human viruses, including hepatitis B and C viruses, agents that frequently establish persistent infection leading to chronic hepatitis, cirrhosis, and liver cancer. However, little is known of the pathways by which hepatocytes, the cell type within which these hepatitis agents replicate, sense infection, and initiate protective responses. We show that cultured hepatoma cells, including Huh7
To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2,890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P < 1 × 10(-5)) in the genome-wide association study were further genotyped in 673 cases and 2,596 controls. We found a previously unidentified locus in the 5' flanking region of MICA on 6p21.33 (rs2596542, P(combined) = 4.21 × 10(-13), odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61) but is significantly associated with progression from CHC to HCC (P = 3.13 × 10(-8)). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P = 1.38 × 10(-13)).
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