A Hyperimmune Serum against a Synthetic Peptide Corresponding to the Hypervariable Region 1 of Hepatitis C Virus Can Prevent Viral Infection in Cell Cultures

Shimizu, Yohko K.; Igarashi, Harukazu; Kiyohara, Tomoko; Cabezón, Teresa; Farci, Patrizia; Purcell, Robert H.; Yasuda, Hiroshi

doi:10.1006/viro.1996.0497

Cited by 173 publications

(131 citation statements)

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“…Consistent with these observations, the HVR1 has been shown to contain at least one neutralization epitope (15,16). In vitro, antibodies to HVR1 can inhibit the binding of recombinant E2 (17) or of virus (18) to cells, and rabbit hyperimmune serum generated to the carboxyl-terminal 21 amino acids of HVR1 can neutralize the infectivity of HCV for chimpanzees (15,16). In addition, a correlation between the early appearance of anti-HVR1 and resolution of HCV infection in acutely infected patients was reported (19)(20)(21).…”

supporting

confidence: 55%

“…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). In vitro, antibodies to HVR1 can inhibit the binding of recombinant E2 (17) or of virus (18) to cells, and rabbit hyperimmune serum generated to the carboxyl-terminal 21 amino acids of HVR1 can neutralize the infectivity of HCV for chimpanzees (15,16).…”

mentioning

confidence: 81%

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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.

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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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supporting

confidence: 55%

mentioning

confidence: 81%

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.

Self Cite

135

121

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“…This region was selected because it is the most variable region of the HCV genome (41) and it has been shown to contain a neutralization domain (50,51). Thus it might be an important target for monitoring the immunologically mediated antiviral effects induced by IFN.…”

Section: Resultsmentioning

confidence: 99%

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Farci

Strazzera²,

Alter³

et al. 2002

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

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Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.

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“…The envelope region studied spanned nucleotides 1099 through 1297 (␣␣ 367-433) contains a putative HLA-A2.1 restricted CTL epitope 20 as well as the HVR (␣␣ 386-412), which contains linear B cell epitopes recognized by neutralizing antibodies (Table 2). [21][22][23] RNA Extraction. Blood was taken at sequential time points over the 2-year period.…”

Section: Methodsmentioning

confidence: 99%

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

et al. 1999

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How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virushost interactions in the selection of HCV mutations.

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A Hyperimmune Serum against a Synthetic Peptide Corresponding to the Hypervariable Region 1 of Hepatitis C Virus Can Prevent Viral Infection in Cell Cultures

Cited by 173 publications

References 0 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

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

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