Association of hepatitis C virus particles with immunoglobulin: a mechanism for persistent infection

Choo, Seungho; So, Hong-Soeb; Cho, Joong Myung; Ryu, Wang Shick

doi:10.1099/0022-1317-76-9-2337

Cited by 56 publications

(50 citation statements)

References 22 publications

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“…Some HCV particles with a high density have been reported to be associated with immunoglobulins (8,15,20,42). To search for immunoglobulins, we subjected the three fractions to SDS-PAGE and Western blotting with anti-immunoglobulin antibodies (Fig.…”

Section: Analysis Of Very-low- Intermediate- and Low-density Plasmamentioning

confidence: 99%

Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA-Containing Particles

André

Komurian-Pradel

Deforges

et al. 2002

J Virol

604

600

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The presence of hepatitis C virus (HCV) RNA-containing particles in the low-density fractions of plasma has been associated with high infectivity. However, the nature of circulating HCV particles and their association with immunoglobulins or lipoproteins as well as the characterization of cell entry have all been subject to conflicting reports. For a better analysis of HCV RNA-containing particles, we quantified HCV RNA in the low-density fractions of plasma corresponding to the very-low-density lipoprotein (VLDL), intermediatedensity lipoprotein, and low-density lipoprotein (LDL) fractions from untreated chronically HCV-infected patients. HCV RNA was always found in at least one of these fractions and represented 8 to 95% of the total plasma HCV RNA. Surprisingly, immunoglobulins G and M were also found in the low-density fractions and could be used to purify the HCV RNA-containing particles (lipo-viro-particles [LVP]). Purified LVP were rich in triglycerides; contained at least apolipoprotein B, HCV RNA, and core protein; and appeared as large spherical particles with a diameter of more than 100 nm and with internal structures. Delipidation of these particles resulted in capsid-like structures recognized by anti-HCV core protein antibody. Purified LVP efficiently bind and enter hepatocyte cell lines, while serum or whole-density fractions do not. Binding of these particles was competed out by VLDL and LDL from noninfected donors and was blocked by anti-apolipoprotein B and E antibodies, whereas upregulation of the LDL receptor increased their internalization. These results suggest that the infectivity of LVP is mediated by endogenous proteins rather than by viral components providing a mechanism of escape from the humoral immune response.

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Section: Analysis Of Very-low- Intermediate- and Low-density Plasmamentioning

confidence: 99%

Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA-Containing Particles

André

Komurian-Pradel

Deforges

et al. 2002

J Virol

604

600

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“…Different buoyant densities of HCV derived from patient sera have been reported. HCVimmunoglobulin complexes from the sera of chronically infected patients exhibit an intermediate density ranging between 1.18 and 1.21 g/ml (12). A second population of HCV with a very low density of ϳ1.08 to 1.11 g/ml in sucrose was observed and most likely represents the infectious form of the virus (10,31,52).…”

mentioning

confidence: 99%

“…Furthermore, the virus population in these sera is very heterogeneous, as viral particles associate with immunoglobulins (12,31,68) and ␤-lipoproteins (52,57,67), complicating direct morphological studies. Different buoyant densities of HCV derived from patient sera have been reported.…”

mentioning

confidence: 99%

Persistent and Transient Replication of Full-Length Hepatitis C Virus Genomes in Cell Culture

Pietschmann

Lohmann

Kaul

et al. 2002

J Virol

330

257

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The recently developed subgenomic hepatitis C virus (HCV) replicons were limited by the fact that the sequence encoding the structural proteins was missing. Therefore, important information about a possible influence of these proteins on replication and pathogenesis and about the mechanism of virus formation could not be obtained. Taking advantage of three cell culture-adaptive mutations that enhance RNA replication synergistically, we generated selectable full-length HCV genomes that amplify to high levels in the human hepatoma cell line Huh-7 and can be stably propagated for more than 6 months. The structural proteins are efficiently expressed, with the viral glycoproteins E1 and E2 forming heterodimers which are stable under nondenaturing conditions. No disulfide-linked glycoprotein aggregates were observed, suggesting that the envelope proteins fold productively. Electron microscopy studies indicate that cell lines harboring these fulllength HCV RNAs contain lipid droplets. The majority of the core protein was found on the surfaces of these structures, whereas the glycoproteins appear to localize to the endoplasmic reticulum and cis-Golgi compartments. In agreement with this distribution, no endoglycosidase H-resistant forms of these proteins were detectable. In a search for the production of viral particles, we noticed that these cells release substantial amounts of nuclease-resistant HCV RNA-containing structures with a buoyant density of 1.04 to 1.1 g/ml in iodixanol gradients. The same observation was made in transient-replication assays using an authentic highly adapted full-length HCV genome that lacks heterologous sequences. However, the fact that comparable amounts of such RNA-containing structures were found in the supernatant of cells carrying subgenomic replicons demonstrates a nonspecific release independent of the presence of the structural proteins. These results suggest that Huh-7 cells lack host cell factors that are important for virus particle assembly and/or release.The hepatitis C virus (HCV) was identified as the causative agent for most posttransfusion and sporadic non-A, non-B hepatitis cases (11,45). According to recent estimates, about 170 million individuals worldwide are infected. One striking characteristic of HCV is its strong propensity to persist in the infected host, which often leads to severe liver damage, ranging from chronic hepatitis to liver cirrhosis and even hepatocellular carcinoma (33). The possible immune evasion strategies that allow persistent viral replication in the presence of the host's immune response are not well understood, but the high variability of the virus appears to be a key determinant (38). As a consequence, HCV isolates exhibit marked sequence diversity and have been grouped according to phylogenetic analysis into six different genotypes which together form the genus Hepacivirus within the family Flaviviridae (60).HCV particles are enveloped, have a diameter of 55 to 65 nm, and harbor an ϳ9,600-nucleotide-long plus-strand RNA genome. It carries a s...

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“…Determination of the buoyant density ofvirus particles showed that the majority of infectivity is found in fractions of 1.03-1.1 g mL-l (Bradley et al, 1991;Carrick et al, 1992;Hijikata et al, 1993a). In addition, particles with lower and higher densities are also detected, corresponding to complexes with cellular lipoproteins and immunoglobulins, respectively (Miyamoto et al, 1992;Hijikata et al, 1993a;Thomssen et al, 1992Thomssen et al, , 1993Choo et al, 1995).…”

Section: Nature Of the Infectious Agentmentioning

confidence: 99%

Molecular Targets in Inhibition of Hepatitis C Virus Replication

Bartenschlager

1997

Antivir Chem Chemother

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SummaryHepatitis C virus (HCY) is the major cause of transfusion-associated hepatitis and accounts for a significant proportion of hepatitis cases worldwide. Most, if not all, infections become persistent and about 60% of cases develop chronic liver disease with various outcomes ranging from an asymptomatic carrier state to chronic active hepatitis and liver cirrhosis, which is strongly associated with the development of hepatocellular carcinoma. Since the initial cloning of the viral genome in 1989, our knowledge of the molecular biology of HCY has increased rapidly and led to the identification of several potential targets for antiviral intervention. In contrast, the low replication of the virus in cell culture, the lack of convenient animal models and the high genome variability present major challenges for drug development. This review will describe candidate drug targets and summarize 'classical' and 'novel' approaches currently being pursued to develop efficient HCYspecific therapies.

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Association of hepatitis C virus particles with immunoglobulin: a mechanism for persistent infection

Cited by 56 publications

References 22 publications

Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA-Containing Particles

Characterization of Low- and Very-Low-Density Hepatitis C Virus RNA-Containing Particles

Persistent and Transient Replication of Full-Length Hepatitis C Virus Genomes in Cell Culture

Molecular Targets in Inhibition of Hepatitis C Virus Replication

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