Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees - PubMed (original) (raw)

Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees

S E Bassett et al. J Virol. 1999 Feb.

Abstract

The relationship of viral persistence, the immune response to hepatitis C virus (HCV) envelope proteins, and envelope sequence variability was examined in chimpanzees. Antibody reactivity to the HCV envelope proteins E1 or E2 was detected by enzyme-linked immunosorbent assay (ELISA) in more than 90% of a human serum panel. Although the ELISAs appeared to be sensitive indicators of HCV infection in human serum panels, the results of a cross-sectional study revealed that a low percentage of HCV-inoculated chimpanzees had detectable antibody to E1 (22%) and E2 (15%). Viral clearance, which was recognized in 28 (61%) of the chimpanzees, was not associated with an antibody response to E1 or E2. On the contrary, antibody to E2 was observed only in viremic chimpanzees. A longitudinal study of animals that cleared the viral infection or became chronically infected confirmed the low level of antibody to E1, E2, and the HVR-1. In 10 chronically infected animals, the sequence variation in the E2 hypervariable region (HVR-1) was minimal and did not coincide with antibody to E2 or to the HVR-1. In addition, low nucleotide and amino acid sequence variation was observed in the E1 and E2 regions from two chronically infected chimpanzees. These results suggest that mechanisms in addition to the emergence of HVR-1 antibody escape variants are involved in maintaining viral persistence. The significance of antibodies to E1 and E2 in the chimpanzee animal model is discussed.

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Figures

FIG. 1

SDS-PAGE analysis of purified E1 and E2 proteins. Western blot analysis of E1 (100 ng) and E2 (5.2 μg) was performed as described in Materials and Methods. Purified E1 (500 ng) and E2 (1.3 μg) were analyzed by SDS-PAGE and silver staining. Recombinant E1 and E2 proteins were purified from _Sf_9 cell lysates by using an agarose G. nivalis (snowdrop) lectin 1 and a Talon metal affinity resin as described in Materials and Methods.

FIG. 2

Antibody response to E1, E2, and the E2 HVR-1. Serial bleeds obtained up to 9 years postinoculation with HCV from chimpanzee x174 were examined by ELISA for reactivity to native, purified E1 and E2, and a synthetic peptide to the HVR-1 as described in Materials and Methods.

FIG. 3

Alignment of amino acid sequences of the E2 HVR-1. The amino acid sequences of the HVR-1s from the acute and chronic phases from 10 chimpanzees are aligned with the amino acid sequence of the HVR from the Hutchinson strain of HCV. Residues identical to the Hutchinson sequence are indicated by a period. Residues differing between the acute and chronic samples are shown in boldface. The clinical records indicate that animals x81, x174, x196, and x62 received the Hutchinson inoculum; animals x204 and x258 received a common inoculum; animals x341 and x342 received a common inoculum, and it is suspected that animal x304 received this inoculum as well. The inoculum for animal x130 was not indicated.

FIG. 4

Relationship of immune responses to envelope proteins and nucleotide changes in the HVR-1. Temporally spaced bleeds from 10 HCV-infected chimpanzees were examined, 5 of which had an antibody response to E2. The HVR-1 sequence was amplified from each serum sample and was cloned and sequenced as described in Materials and Methods. The sera were examined by ELISA for antibody to E1 and E2. Positive responses are indicated by a “+” at the top of the bars. The bars represent the OD values from the E1 and E2 ELISAs of paired sera, with the earliest and latest bleeds represented by the bars to the left and right, respectively. The chimpanzee numbers, the duration of time between temporally spaced sera, and the number of nucleotide and amino acid changes are noted at the bottom.

References

1. Abe K, Inchauspe G, Fujisawa K. Genomic characterization and mutation rate of hepatitis C virus isolated from a patient who contracted hepatitis during an epidemic of non-A, non-B hepatitis in Japan. J Gen Virol. 1992;73:2725–2729. - PubMed
1. Abe K, Inchauspe G, Shikata T, Prince A M. Three different patterns of hepatitis C virus infection in chimpanzees. Hepatology. 1992;15:690–695. - PubMed
1. Abrignani S. Immune responses throughout hepatitis C virus (HCV) infection: HCV from the immune system point of view. Springer Semin Immunopathol. 1997;19:47–55. - PubMed
1. Allander T, Beyene A, Jacobson S H, Grillner L, Persson M A A. Patients infected with the same hepatitis C virus strain display different kinetics of the isolate-specific antibody response. J Infect Dis. 1997;175:26–31. - PubMed
1. Alter H J. To C or not to C: these are the questions. J Am Soc Hematol. 1995;85:1681–1695. - PubMed

Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees - PubMed (original) (raw)