Intrahepatic Genetic Inoculation of Hepatitis C Virus RNA Confers Cross-Protective Immunity

Weiner, Amy J.; Paliard, Xavier; Selby, Mark; Medina-Selby, Angelica; Coit, Doris; Nguyen, Steve; Kansopon, Joe; Arian, Christopher L.; Ng, Philip; Tucker, Jeffery; Lee, Chun-Ting; Polakos, Noelle K.; Han, Jang H.; Wong, Stephanie E.; Lu, Hui-Hua; Rosenberg, Steve; Brasky, Kathy; Chien, David; Kuo, George; Houghton, Michael

doi:10.1128/jvi.75.15.7142-7148.2001

Cited by 84 publications

(47 citation statements)

References 52 publications

(44 reference statements)

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“…Other investigators reported rapid control of HCV in chimpanzees that were rechallenged with homologous monoclonal or polyclonal virus (17,21,25,29,33). Taken together, these studies found that viral clearance was associ-FIG.…”

supporting

confidence: 55%

Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain

Bukh

Thimme

Meunier

et al. 2008

J Virol

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Protective immunity after resolved hepatitis C virus (HCV) infection has been reported. However, the breadth of this immunity has remained controversial, and the role of neutralizing antibodies has not been well-defined. In the present study, two chimpanzees (CH96A008 and CH1494) with resolved monoclonal H77C (genotype 1a) infection were rechallenged with low-dose homologous H77C virus about 12 months after viral clearance; CH96A008 became persistently infected, and CH1494 had transient viremia lasting 2 weeks. CH1494 was subsequently either partially or completely protected following five homologous rechallenges with monoclonal H77C or polyclonal H77 and after six heterologous rechallenges with HC-J4 (genotype 1b) or HC-J6 (genotype 2a) viruses. Subsequently, a final challenge with H77C resulted in persistent HCV infection. In both chimpanzees, serum neutralizing antibodies against retroviral pseudoparticles bearing the H77C envelope proteins were not detected during the initial infection or during rechallenge. However, anamnestic cellular immune responses developed during the initial homologous rechallenge, in particular in CH96A008, which developed a persistent infection. Polyprotein sequences of viruses recovered from CH1494 after the two homologous rechallenges that resulted in transient viremia were identical with the H77C virus. In contrast, the polyprotein sequences of viruses recovered from both chimpanzees after homologous rechallenge resulting in persistent infection had numerous changes. These findings have important implications for our understanding of immunity against HCV; even in the best-case scenario with autologous rechallenge, low-level viral persistence was seen in the presence of primed T-cell responses.

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supporting

confidence: 55%

Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain

Bukh

Thimme

Meunier

et al. 2008

J Virol

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“…It is interesting to note that HCVspecific cellular immune responses are detectable earlier after rechallenge (2 weeks) than after primary infection (8-10 weeks). 39,41,128,131 This acceleration of the adaptive immune response, although insufficient to prevent infection, can influence positively the course of the HCVinduced liver disease in vaccinated animals, which usually develop low viremia and mild hepatitis. These findings in HCV rechallenge experiments and in HCV-vaccinated animals reinforce the hypothesis that the long interval of time between infection and activation of the HCVspecific adaptive immune response represents a major factor that influences the rate of chronicity and the profile of the disease.…”

Section: Final Remarksmentioning

confidence: 99%

“…123,124 Moreover, although a vaccine based on the envelope protein of HBV, which induces envelope-specific antibody 122 and helper T-cell responses, [125][126][127] can elicit a sterilizing anti-HBV immunity, different HCV vaccine preparations able to prime similar profiles of T-and B-cell responses have so far failed to protect animals from HCV infection. 128,129 The different kinetics of HCV and HBV replication may represent one of the factors responsible for these differences. If HCV can survive the neutralizing effect of anti-HCV envelope antibodies 32,130 that persist at low levels after natural HCV infection 37 or immunization, 129 a reservoir of replicating virus can be established immediately that may outpace the development of recall HCV-specific antibody and T-cell responses.…”

Section: Final Remarksmentioning

confidence: 99%

Kinetics of the immune response during HBV and HCV infection

2003

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The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge. (HEPATOLOGY 2003; 38:4-13.)H epatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide. 1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] These responses are stronger than those found in patients with chronic infection. [17][18][19][20][21] Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity. 2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found, 23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8 ϩ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection. 24 These results have been confirmed by recent reports showing that expansion of interferon ␥ (IFN-␥) ϩ , CD8 ϩ , and CD4 ϩ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man 10 and in HCV-infected chimpanzees. 25 Similar findings have been reported in animal models of HBV infection 26 and in patients studied during the incubation phase of HBV infection, 27 in whom reduced early expansion of virusspecific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8 ϩ T cells in HBV control has been confirmed further by CD8 ϩ T-cell deletion experiments performed in HBV-i...

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“…4,5 However, we and others have shown that following rechallenge, viremia and liver disease are significantly reduced in both intensity and duration [6][7][8] ; this appears to be mediated through faster T-cell activation in peripheral blood and liver in chimpanzees 8,9 and possibly in humans. 10 Despite developments with transgenic mouse systems using transplanted human hepatocytes, 11 the only established animal model for HCV is the chimpanzee, 12 which makes challenge vaccine experiments difficult and expensive.…”

mentioning

confidence: 99%

CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus

Puig¹,

Mihalik²,

Tilton³

et al. 2006

Hepatology

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Hepatitis C is a major cause of chronic liver disease, with 170 million individuals infected worldwide and no available vaccine. We analyzed the effects of an induced T-cell response in 3 chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. In all animals the specific T-cell response modified the outcome of infection, producing a 10-to 1,000-fold reduction in peak virus titers. The challenge of 2 immunized animals that had been previously exposed to hepatitis C virus resulted in subclinical infections. Immune responses in the third animal, naive prior to immunization, limited viral replication immediately, evidenced by a 30-fold reduction in virus titer by week 2, declining to a nonquantifiable level by week 6. After 10 weeks of immunological control, we observed a resurgence P ersistent infections caused by hepatitis C virus (HCV) occur in 70%-80% of the acutely infected population, most of whom will develop chronic hepatitis and be at risk for cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma. 1 Antiviral therapy at present is successful in about 50% of patients, but treatment carries significant side effects and is very costly. 2,3 At present, about 25,000 new HCV infections occur each year in the United States, making the development of a vaccine against this virus imperative.Natural infection with HCV had previously been thought to afford no protective immunity from reinfection. 4,5 However, we and others have shown that following rechallenge, viremia and liver disease are significantly reduced in both intensity and duration 6-8 ; this appears to be mediated through faster T-cell activation in peripheral blood and liver in chimpanzees 8,9 and possibly in humans. 10 Despite developments with transgenic mouse systems using transplanted human hepatocytes, 11 the only established animal model for HCV is the chimpanzee, 12 which makes challenge vaccine experiments difficult and expensive. The development of HCV vaccines has also been hampered by the lack of an effective in vitro cell culture

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Intrahepatic Genetic Inoculation of Hepatitis C Virus RNA Confers Cross-Protective Immunity

Cited by 84 publications

References 52 publications

Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain

Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain

Kinetics of the immune response during HBV and HCV infection

CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus

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