Lack of Protective Immunity Against Reinfection with Hepatitis C Virus

Farci, Patrizia; Alter, Harvey J.; Govindarajan, Sugantha; Wong, Doris C.; Engle, Ronald E.; Lesniewski, Richard R.; Mushahwar, Isa K.; Desai, Suresh M.; Miller, R.H.; Ogata, Norio; Purcell, Robert H.

doi:10.1126/science.1279801

Cited by 710 publications

(223 citation statements)

References 49 publications

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“…Both animals not only became infected with HCV but also developed hepatitis. Although reinfection of previously infected chimpanzees with HCV is widely recognized, such infections seldom result in hepatitis (24). Thus, the demonstration of hepatitis in these two rechallenged chimpanzees is strong evidence that they were not infected previously.…”

Section: Prevention Of Hcv Infection In Chimpanzees By Experimental Igivmentioning

confidence: 80%

Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma

Bartosch

Zhang

et al. 2004

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

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143

115

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The role of humoral immunity in hepatitis C virus (HCV) infections is uncertain. Nevertheless, there is increasing evidence for neutralizing antibodies to HCV in the serum or plasma of chronically infected individuals. Immune globulins prepared by ethanol fractionation of plasma had long been considered safe until a commercial immune globulin product, Gammagard, prepared from plasma from which units containing anti-HCV had been excluded, transmitted HCV to recipients. Studies suggested that the exclusion might have removed neutralizing antibodies from the plasma and hence compromised the safety of the resulting immune globulins. In the present study, by using chimpanzees and a recently validated in vitro system based on neutralization of infectious HCV pseudoparticles, we found broadly reactive neutralizing and protective antibodies in experimental immune globulin preparations made from anti-HCV-positive donations. Neutralizing antibodies were also found in Gammagard lots made from unscreened plasma that did not transmit hepatitis C but not in Gammagard lots, which were prepared from anti-HCV-screened plasma, that did transmit hepatitis C. The results provide an explanation for the mechanism by which the safety of this product was compromised. Immune globulins made from anti-HCV-positive plasma and containing broadly reactive neutralizing antibodies may provide a method of preventing HCV infection.

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Section: Prevention Of Hcv Infection In Chimpanzees By Experimental Igivmentioning

confidence: 80%

Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma

Bartosch

Zhang

et al. 2004

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

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143

115

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“…There were no significant differences in baseline histology or alanine aminotransferase level (mean Ϯ SD, 147.6 Ϯ 68.3) among the different patient groups. All patients were positive for anti-HCV antibodies by thirdgeneration ELISA assay and for serum HCV RNA as measured by a nested reverse transcription-PCR (39) using two sets of primers from the 5Ј noncoding region (40). All were negative for hepatitis B surface antigen and antibodies to HIV type 1 (HIV-1).…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from 100 l of serum and reverse-transcribed in a volume of 20 l, and the resulting cDNA was amplified by using sets of primers from the E1 and E2 genes, including the HVR1 (40). The sensitivity, specificity, and details of our nested PCR technique have been reported (39).…”

Section: Methodsmentioning

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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195

186

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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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“…11,12 This may of overlapping peptides covering most of E2. This serum be because of the presence of multiple quasispecies in the contained antibodies recognizing two distinct epitopes inoculum.…”

mentioning

confidence: 99%

A specific antibody response to HCV E2 elicited in mice by intramuscular inoculation of plasmid DNA containing coding sequences for E2

Tedeschi

1997

Hepatology

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posed to direct peptide immunizations, this method allows As the chimpanzee, the only reliable animal model for host processing of newly synthesized viral proteins, which hepatitis C virus (HCV) infection, is impractical for early includes ensuring correct glycosylation and conformation of stage testing of HCV vaccine candidates, we have evaluthe proteins and proteolytic processing, known to be key facated the immune response in mice to an experimental tors in both humoral and cellular immune responses. Endogeplasmid based HCV vaccine. We used this system benous antigen processing may also lead to appropriate antigen cause DNA vaccines can be rapidly constructed without presentation by major histocompatibility complex class I and the necessity of large scale protein production and puriclass II molecules, an essential feature in T-cell recognition fication. In this preliminary study we tested the immune of the antigen. response in mice to HCV envelope glycoprotein, E2, inWhile the need for hepatitis C prevention is clear, a path duced by a eukaryotic expression plasmid. Protein exfor vaccine development is not. There exists support for the pression was monitored by immunofluorescence in concept that the hypervariable domain (HVR1) near the Ntransfected tissue culture cells. Each mouse was inocuterminus of E2 is an important neutralization site. However, lated intramuscular with 100 mg plasmid DNA and some genetic variability within this region may allow the virus to mice were boosted after 5 weeks. Among 12 BALB/C mice escape immune surveillance. 7-10 It has been difficult to show inoculated, 10 developed antibody to E2 by the second immune protection in either humans or experimentally inweek. The antibody levels increased steadily before fected chimpanzees. Cross-challenge experiments and even reaching a plateau in mice receiving the booster, but in rechallenge experiments in which chimpanzees were inocuthe nonboosted mice the antibody declined over time.lated several times with the same inoculum have shown that The serum from one mouse was tested against a series there is not solid immunity following infection. 11,12 This may of overlapping peptides covering most of E2. This serum be because of the presence of multiple quasispecies in the contained antibodies recognizing two distinct epitopes inoculum. On the other hand, experimental vaccines probeginning at amino acid 57 and amino acid 113 but no duced from synthetic envelope glycoproteins have been antibody was directed against peptides representing the shown to induce at least a low-level protection in chimpanhypervariable region of E2, antibody to which is thought zees against a homotypic challenge. 13 In addition, cellular to be important in HCV neutralization. We have shown immune responses to E2 have been reported 14,15 and these that the use of plasmid based vaccines can induce a spemay play a role in protection or recovery from hepatitis C cific immune response in mice against HCV antigens.virus (HCV) infection. This system should be useful as the fir...

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Lack of Protective Immunity Against Reinfection with Hepatitis C Virus

Cited by 710 publications

References 49 publications

Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma

Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma

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

A specific antibody response to HCV E2 elicited in mice by intramuscular inoculation of plasmid DNA containing coding sequences for E2

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