E2/nonstructural protein 1, the putative envelope glycoprotein (gp72) of HCV, possesses an N-terminal hypervariable (E2 HV) domain from amino acids 384 to 414 of unknown sinificance. The high degree of amino acid sequence variation in the E2 HV domain appears to be comparable to that observed in the human immunodeficiency virus type 1 gp120 V3 domain. This observation and the observation that the HCV E2 HV domain lacks conserved secondary structure imply that, like the V3 loop of human immunodeficiency virus 1 gpl20, the N-terminal E2 region may encode protective epitopes that are subject to immune selection. Antibodyepitope binding studies revealed five isolate-specific linear epitopes located in the E2 HV region. These results suggest that the E2 HV domain is a target for the human immune response and that, in addition to the three major groups ofHCV, defined by nucleotide and amino acid sequence identity among HCV isolates, E2 HV-specific subgroups also exist. Analysis of the partial or complete E2 sequences of two individuals indicated that E2 HV variants can either coexist simultaneously in a single individual or that a particular variant may predominate during different episodes of disease. In the latter situation, we found one individual who developed antibodies to a subregion ofthe E2 HV domain (amino acids 396-407) specific to a variant that was predominant during one major episode ofhepatitis but who lacked detectable antibodies to the corresponding region of a second variant that was predominant during a later episode of disease. The data suggest that the variability in the E2 HV domain may result from immune selection. The fings of this report could impact vaccine strategies and drug therapy programs designed to control and eliminate HCV.HCV is the major etiologic agent oftransfusion-associated and community-acquired non-A, non-B hepatitis on several continents (1-3). A high rate ofchronic hepatitis is associated with HCV infections (4, 5). Two patterns of HCV-associated chronic liver disease have been described in humans and chimpanzees (4 tTo whom reprint requests should be addressed. 3468The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Hepatitis C virus (HCV) establishes a persistent infection in humans and chimpanzees despite the presence of virus-specific, class I major histocompatibility complex-restricted CD8+ cytotoxic T lymphocytes (CTLs) in the liver. The data presented here demonstrate that CTLs directed against a conserved epitope in the HCV nonstructural 3 protein persist in the liver of a chronically infected chimpanzee for at least 2 years after infection. However, these CTLs did not recognize the HCV quasi-species present in the plasma of this animal at week 16 postinfection or at later time points. Escape from the CTL response was facilitated by an aspartic acid to glutamic acid (D -> E) substitution at amino acid position 1449 in all HCV genomes that were sequenced. The results of this study strongly support the concept that CTL responses can select for variant viruses with an enhanced ability to persist in a host and have important implications for the design of vaccines against HCV.Hepatitis C virus (HCV), a positive strand RNA virus belonging to the Flaviviridae, is the major etiologic agent of bloodborne and sporadic community-acquired non-A, non-B hepatitis (reviewed in ref. 1). The outcome of HCV infection is variable. Acute hepatitis C is successfully resolved in some individuals, but many develop a persistent infection that is not controlled by virus-specific humoral (2-4) or cellular (5-12) immune responses. Persistence of HCV is surprising in light of a strong HCV-specific, class I major histocompatibility complex (MHC)-restricted cytotoxic T-lymphocyte (CTL) response in chronically infected humans (8-11) and chimpanzees (12). It has been postulated that this cytolytic activity contributes to liver inflammation (13), but it is not clear why the infected hepatocytes are not eventually eliminated. Potential mechanisms for evasion of CTL surveillance include persistence of the virus in an immunologically privileged, extrahepatic site, restricted expression ofviral or class I MHC proteins in infected hepatocytes, or emergence of virus variants with mutations in CTL epitopes, possibly as a result of immune system selection pressure (14,15).The RNA genome of HCV is highly mutable (16)(17)(18)(19), with a genetic drift rate of 10-3 to 10-4 nucleotide substitutions per site per year. Rapid evolution of HCV may facilitate the generation of variants that escape recognition by anti-HCV antibodies (20)(21)(22)(23)
Mutants of cdc2+ can disrupt the dependency of S phase on completion of the previous mitosis. By changing the state of p34cdc2 it is possible to reprogramme a cell from entering mitosis to undergoing S phase. This leads to the proposal that the cell cycle can be considered a p34cdc2 cycle, and has implications for the evolution of life cycles.
Expression cloning of cDNAs encoding a basic fibroblast growth factor (FGF) binding protein confirms previous hypotheses that this molecule is a cell-surface heparan sulfate proteoglycan. A cDNA library constructed from a hamster kidney cell line rich in FGF receptor activity was transfected into a human lymphoblastoid cell line. Clones expressing functional basic FGF binding proteins at their surfaces were enriched by panning on plastic dishes coated with human basic FGF. The amino acid sequence deduced from the isolated cDNAs revealed several interesting features, including hydrophobic signal and transmembrane domains that flank an extracellular region containing six potential attachment sites for glycosaminoglycan side chains. The structure also contains a short hydrophilic cytoplasmic tail sequence homologous to previously reported actin binding domains. Binding of basic FGF to cells expressing the binding protein could be inhibited by heparin and heparan sulfate but not by chondroitin sulfate, dermatan sulfate, or keratan sulfate. In addition to binding basic FGF, this protein or related surface proteins may function as an initial cellular attachment site for other growth factors and for viruses, such as herpes simplex virus.
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