Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity

Tsai, Shau‐Wei; Chen, Young-Mao; Chen, Ming-Huei; Huang, Chung-Chi; Sheen, I‐Shyan; Yeh, Chau‐Ting; Huang, Jiansheng; Kuo, George; Liaw, Yun–Fan

doi:10.1016/s0016-5085(98)70268-9

Cited by 136 publications

(117 citation statements)

References 71 publications

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“…This region has been extensively used to characterize the quasispecies nature of HCV (7)(8)(9)(10). It evolves rapidly in infected individuals, suggesting that it is under strong immune pressure, and there is evidence that the virus is able to escape the host immune response by accumulating mutations in the HVR1 region (11)(12)(13)(14). Consistent with these observations, the HVR1 has been shown to contain at least one neutralization epitope (15,16).…”

mentioning

confidence: 82%

Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees

Forns

Thimme

Govindarajan

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

135

121

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Persistent infection with hepatitis C virus (HCV) is among the leading causes of chronic liver disease. Previous studies suggested that genetic variation in hypervariable region 1 (HVR1) of the second envelope protein, possibly in response to host immune pressure, influences the outcome of HCV infection. In the present study, a chimpanzee transfected intrahepatically with RNA transcripts of an infectious HCV clone (pCV-H77C) from which HVR1 was deleted became infected; the ⌬HVR1 virus was subsequently transmitted to a second chimpanzee. Infection with ⌬HVR1 virus resulted in persistent infection in the former chimpanzee and in acute resolving infection in the latter chimpanzee. Both chimpanzees developed hepatitis. The ⌬HVR1 virus initially replicated to low titers, but virus titer increased significantly after mutations appeared in the viral genome. Thus, wild-type HCV without HVR1 was apparently attenuated, suggesting a functional role of HVR1. However, our data indicate that HVR1 is not essential for the viability of HCV, the resolution of infection, or the progression to chronicity.

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mentioning

confidence: 82%

Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees

Forns

Thimme

Govindarajan

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

135

121

View full text Add to dashboard Cite

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“…The HVR-1 of HCV is a major immunogenic domain, bears major neutralizing epitopes (Kato et al, 1993;Shimizu et al, 1994), and evolutionary changes of this region are believed to have important implications in viral persistence and pathogenicity (Gretch et al, 1996;Kato et al, 1994;McAllister et al, 1998;Tsai et al, 1998). The role of the ISDR in the response to interferon is still a matter of controversy (Brechot, 1999;Enomoto et al, 1996;Hoofnagle, 1997;Sá iz et al, 1998), but this region seems to modulate the interferon transduction pathway by interacting with a cellular protein kinase (Gale et al, 1997(Gale et al, , 1998.…”

Section: Hcv Genotype and Evolution In Paraffin Livermentioning

confidence: 99%

Assessment of Genotype and Molecular Evolution of Hepatitis C Virus in Formalin-Fixed Paraffin-Embedded Liver Tissue from Patients With Chronic Hepatitis C Virus Infection

Soguero

Campo

Ribalta

et al. 2000

Laboratory Investigation

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SUMMARY:Drawbacks of hepatitis C virus (HCV) RNA detection in paraffin-embedded liver tissue have satisfactorily been solved by RT-PCR amplification of the 5Јnon-coding region (5ЈNCR). However, detection of this highly conserved region does not provide information on epidemiological or pathogenetic aspects of HCV infection. This study explores whether other functionally important genetic regions of HCV, such as the hypervariable region 1 (HVR-1) and the interferon sensitivity-determining region (ISDR), can be retrieved from paraffin-embedded liver specimens by RT-PCR, and whether the amplified material is suitable for further molecular analyses. RT-PCR amplification of 5ЈNCR, HVR-1, and ISDR was assessed in RNA extracted from 50 formalin-fixed, paraffin-embedded liver specimens, including 23 needle liver biopsies (11 from patients with non-A, non-B chronic hepatitis diagnosed between 1971 and 1985, 8 from subjects with normal liver histology and 4 from sequential biopsies from a patient with HCV recurrence after liver transplantation), and 27 liver explants from patients undergoing transplantation between 1988 and 1996 (16 with HCV-related cirrhosis and 11 with other disorders). The 5ЈNCR was successfully amplified in 8 of 11 (73%) non-A, non-B chronic hepatitis biopsies and in all of the specimens from patients with serological documentation of HCV infection. There were no false-positive results. HCV genotype was identified by RFLP analysis of the 5ЈNCR in the 13 cases analyzed. HVR-1 and ISDR were amplified in 24 of 28 (86%) samples, which were positive for the 5ЈNCR. Efficient amplification was inversely related to the time of storage. The evolutionary changes of HVR-1 and ISDR were successfully analyzed by direct sequencing of amplificates from the explanted liver and from the sequential liver biopsies in a patient with HCV infection recurrence after transplantation. These observations indicate that paraffin-embedded liver tissue, even when stored for more than 20 years, is appropriate for advanced studies on the molecular biology of HCV. (Lab Invest 2000, 80:851-856).

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“…[5][6][7][8][9][10][11][12] The CD8 ϩ T-cell response to HCV may be only partially successful in virus control because it is quantitatively inadequate, [13][14][15][16][17] and it may also select for immune escape variants that further contribute to viral persistence. 13,[18][19][20] The role of CD8 ϩ T cells in this infection is most clearly illustrated, perhaps, in experimentally infected chimpanzees where a multispecific intrahepatic HCV-specific CD8 ϩ T-cell response during the early phase of infection was associated with subsequent HCV clearance while a more narrowly focused and delayed response was associated with persistent infection. 21 In contrast to these results, however, the relationship between the HCV-specific CD8 ϩ T-cell response and the outcome of infection in humans is not well understood.…”

mentioning

confidence: 99%

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

2001

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This study was performed to compare the vigor and phenotype of virus-specific CD4 ؉ and CD8 ؉ T-cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4 ؉ proliferative T-cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV-specific CD8 ؉ T-cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN-␥) staining. Furthermore, although HCV-specific cytolytic CD8 ؉ memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV-infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV-specific memory CD8 ؉ T-cell response. HCV-specific CD8 ؉ T cells displayed a type 1 cytokine profile characterized by production of IFN-␥ despite persistent HCV viremia. The paradoxical observation that HCV-specific CD4 ؉ T cells survive and CD8 ؉ T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4 ؉ and CD8 ؉ T-cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8 ؉ effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus. (HEPATOLOGY 2001;33:267-276.)Hepatitis C virus (HCV) is a parenterally transmitted hepatotropic RNA virus that causes acute and chronic hepatitis. 1,2 While acute infection is generally subclinical, and therefore difficult to identify, chronic infection occurs in the majority of cases, and this can be associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 3,4 The role of CD4 ϩ and CD8 ϩ T cells in HCV clearance or disease pathogenesis is not well understood. Certainly, persistent infection occurs despite the presence of virus-specific CD4 ϩ and CD8 ϩ T cells in the liver and the peripheral blood, suggesting that these responses are ineffective in most patients. [5][6][7][8][9][10][11][12] The CD8 ϩ T-cell response to HCV may be only partially successful in virus control because it is quantitatively inadequate, [13][14][15][16][17] and it may also select for immune escape variants that further contribute to viral persistence. 13,[18][19][20] The role of CD8 ϩ T cells in this infection is most clearly illustrated, perhaps, in experimentally infected chimpanzees where a multispecific intrahepatic HCV-specific CD8 ϩ T-cell response during the early phase of infection was associated with subsequent HCV clearance while a more narrowly focused and delayed response was associated with persistent infection. 21 In contrast to these results, however, the relationship between the HCV-specific CD8 ϩ T-cell response and the outcome of infection...

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Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity

Cited by 136 publications

References 71 publications

Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees

Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees

Assessment of Genotype and Molecular Evolution of Hepatitis C Virus in Formalin-Fixed Paraffin-Embedded Liver Tissue from Patients With Chronic Hepatitis C Virus Infection

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

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