Modulation of the peripheral T-Cell response by CD4 mutants of hepatitis C virus: transition from a Th1 to a Th2 response

Wang, H; Layden, Thomas J.; Eckels, David D.

doi:10.1016/s0198-8859(03)00070-3

Cited by 46 publications

(56 citation statements)

References 75 publications

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“…44 NS3-specific CD4ϩ escape mutants have been identified in patients. The variants attenuate or fail to stimulate T-cell proliferation, 45 which is consistent with our observation of T-cell proliferation in Ch6394 after the emergence of mutations in NS3 and NS5A.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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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“…The cytokine profile of this clone had the signature of a Th2͞Treg type of a CD4 ϩ T cell, which is compatible with what has also been reported in T1D patients and HLA-DR4-positive humans with ␤-islet cell autoimmunity (5,9,21). A similar drift from early T cell proliferation and IFN␥ responses over a stage with continued antigen-specific T cell proliferation with a shift to predominant IL-10 production (but without T cell proliferation) has also been reported in hemophiliac patients during the evolution of hepatitis C virus (HCV) infection (22). These hemophiliac patients, who, aside from their coagulation defect are healthy, did, over time, develop chronic HCV disease with loss of viral control.…”

Section: Discussionsupporting

confidence: 85%

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Durinovic‐Belló

Rosinger

Ja³

et al. 2006

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

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Recently, we have identified proinsulin (P-Ins)73-90 as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with ␤-islet cell autoimmunity and of HLA-DR4͞CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)͞HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFN␥ in response to P-Ins73-90. This finding is compatible with the previously detected regulatory cytokine pattern in subjects with ␤-cell autoimmunity. However, added N-or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins 73-90-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with ␤-islet cell autoimmunity or recent-onset type 1 diabetes.Foxp3 ͉ HLA-DRB1*0401 ͉ type 1 diabetes P roinsulin (P-Ins) is considered an important autoantigen in type 1 diabetes (T1D), because it is the only truly ␤-cellspecific target, and because autoreactivity to P-Ins is very common in T1D patients with the HLA-DRB1*0401 (DR4) DQ8 haplotype (1-6). The differences distinguishing autoreactive from foreign antigen reactive T cell responses to the same immunogenic epitope are still largely unknown (7). To understand the structural requirements for activation of self-reactive P-Ins 73-90 -specific T cells in T1D autoimmunity, we have isolated a Foxp3-positive CD4 ϩ T cell clone from a DR4-homozygous T1D patient and compared the fine specificity of this T cell receptor to those of two murine T cell hybridoma clones derived from HLA-DR4 transgenic mice, in which this epitope is a foreign antigen (8). P-Ins 73-90 is situated at the C terminus of the C peptide and also covers the enzymatic cleavage site of the insulin A chain (8). This site is proteolytically destroyed during the maturation of insulin before secretion and is, therefore, an indication that Proinsulin and not Insulin may be the actual autoantigenic target in T1D.In human studies using purified CD4 ϩ T cells from HLA-DR4-positive subjects with islet autoimmunity, P-Ins 73-90 was also identified as an immunodominant epitope. This epitope was recognized by approximately two thirds of autoantibody-positive subjects, one third of recently diagnosed T1D patients, and a few control subjects (5, 9). The cytokines seen in response to P-Ins 73-90 were predominantly IL-4 and IL-10 in subjects with ␤-cell autoimmunity (9). Moreover, in a consecutive follow up of three high-risk individuals, ...

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“…While HBV evasion strategies are focused primarily on the adaptive immune response, HCV has developed mechanisms that appear designed to enable it to escape both the innate and the adaptive response. As shown in Table 1, mutational escape from the adaptive response due to its high mutation rate is common in HCV-infected patients and chimpanzees (35,36,52,136,153,162,163,169,170). In addition, however, because it replicates via a dsRNA intermediate, HCV activates protein kinase R (113), interferon regulatory factor 1 (IRF-1) (42,113), and IRF-3 (42,143), and downstream antiviral genes that were originally shown to be activated by these factors in different viral infections (reviewed in references 14 and 141).…”

Section: Viral Factorsmentioning

confidence: 99%

Stealth and Cunning: Hepatitis B and Hepatitis C Viruses

Wieland

Chisari

2005

J Virol

414

360

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The hepatitis B virus (HBV) and hepatitis C virus (HCV) are noncytopathic, hepatotropic members of the hepadnavirus (HBV) and flavivirus (HCV) families that cause acute and chronic necroinflammatory liver disease and hepatocellular carcinoma (HCC) (29,38,79). On a worldwide basis, over 500 million people are persistently infected by these viruses and are at great risk of dying prematurely from HCC (29,64,79,111). It is widely believed that the outcome of both infections and the pathogenesis of the associated liver diseases are determined by host-virus interactions mediated by the immune response. It has been difficult to elucidate the viral and host factors at play in these infections, however, largely because the host range of HBV and HCV is limited to humans and chimpanzees (3, 19) and because cell culture systems and small animal models that are susceptible to HBV and HCV infection do not exist. Thus, the current state of our understanding of the biology and pathogenesis of these infections reflects what has been learned about their natural history (47, 64) and immunobiology (29, 137) in humans and chimpanzees, by the virological and immunological analysis of related hepadnavirus (131) and flavivirus (18) infections in their natural hosts, and by biochemical, molecular, virological, and immunological analysis of cell lines (5,15,67,73,76,88,89,100,109,114,135,174) and mouse models that express individual viral genes or reproduce the viral life cycles to various degrees (30,33,56,63,74,75,77,83,90,101,102,107,110,161). Thanks to these efforts, in recent years we have gained important new insight into the viral and host factors that determine pathogenesis and outcome of HBV and HCV infection. As we will describe in this review, it now appears that HBV is a stealth virus that establishes itself very efficiently without alerting the innate immune system to its presence, although it is readily controlled when the adaptive immune response is induced. In contrast, HCV strongly induces yet cunningly evades the innate immune response and also defeats the adaptive immune response by mutation and functional inactivation. VIRAL FACTORSAlthough host factors contribute importantly to the outcome of HBV and HCV infection, viral factors are also critically involved. Perhaps the strongest evidence that viral factors play a role in the outcome of HBV and HCV infection is that more than 95% of adult-onset HBV infections are self limited, while more than 70% of adult-onset HCV infections persist, and the outcomes for humans and chimpanzees are similar (19,81,145,149,151). Moreover, as illustrated in Fig. 1, we have recently shown that chimpanzees that have previously cleared HBV (58) (Fig. 1, upper panels) become persistently infected when subsequently inoculated with HCV ( Fig. 1, lower panels) (149). These results suggest that the different outcomes of infection could not be due to host genetic differences in these animals. Figure 1 also demonstrates an interesting and underappreciated difference between HBV and HCV, i.e., tha...

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Modulation of the peripheral T-Cell response by CD4 mutants of hepatitis C virus: transition from a Th1 to a Th2 response

Cited by 46 publications

References 75 publications

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

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

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Stealth and Cunning: Hepatitis B and Hepatitis C Viruses

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