Type 1 interferon augments DNA‐based vaccination against hepatitis C virus core protein

Gehring, Stephan; Gregory, Stephen H.; Kuzushita, Noriyoshi; Wands, Jack R.

doi:10.1002/jmv.20264

Cited by 32 publications

(27 citation statements)

References 38 publications

(39 reference statements)

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“…It is possible that the abnormal CD8 ϩ T cell response in IRF7 KO mice is due to the lack of type I IFNs. To test this hypothesis, IRF7 KO mice were infected with LCMV followed by three injections of recombinant universal interferon-␣ A/D (hybrid interferon-␣ A/D), which is functional in mice (14,38). On day 9 p.i., CD8 ϩ T cells were analyzed by ICS for expression of IFN-␥.…”

Section: Addition Of Exogenous Recombinant Type I Ifn Restores Cd8mentioning

confidence: 99%

Role of Interferon Regulatory Factor 7 in T Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection

Zhou

Cerny

Fitzgerald

et al. 2012

J Virol

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Type I interferons (IFNs), predominantly IFN-␣ and -␤, play critical roles in both innate and adaptive immune responses against viral infections. Interferon regulatory factor 7 (IRF7), a key innate immune molecule in the type I IFN signaling pathway, is essential for the type I IFN response to many viruses, including lymphocytic choriomeningitis virus (LCMV). Here, we show that although IRF7 knockout (KO) mice failed to control the replication of LCMV in the early stages of infection, they were capable of clearing LCMV infection. Despite the lack of type I IFN production, IRF7 KO mice generated normal CD4 ؉ T cell responses, and the expansion of naïve CD8 ؉ T cells into primary CD8 ؉ T cells specific for LCMV GP 33-41 was relatively normal. In contrast, the expansion of the LCMV NP 396 -specific CD8 ؉ T cells was severely impaired in IRF7 KO mice. We demonstrated that this defective CD8؉ T cell response is due neither to an impaired antigen-presenting system nor to any intrinsic role of IRF7 in CD8 ؉ T cells. The lack of a type I IFN response in IRF7 KO mice did not affect the formation of memory CD8 ؉ T cells. Thus, the present study provides new insight into the impact of the innate immune system on viral pathogenesis and demonstrates the critical contribution of innate immunity in controlling virus replication in the early stages of infection, which may shape the quality of CD8 ؉ T cell responses. Induction of type I interferons (IFNs) is not only essential for host innate immunity against viral pathogens but also critically involved in the development of virus-specific adaptive immune responses, in particular, T cell responses. Activation of naïve T cells occurs through three signals: the peptide-major histocompatibility complex (MHC) (signal 1), costimulatory molecules on antigen-presenting cells (APCs) (signal 2), and immunoregulatory cytokines (signal 3) (16). Type I IFNs are involved in regulating all three signals and can also directly act on T cells by interacting with the IFN-␣/␤ receptor on T cells to provide survival signals (7,26,29,31). In addition, in vitro studies have shown that IFN-␣ coordinately regulates lymphocytic choriomeningitis virus (LCMV)-specific CD8 ϩ T cell activation (38, 41). Studies suggest that type I IFN production is controlled by a group of transcriptional factors, including nuclear factor B (NF-B) and the interferon regulatory factors (IRFs) (19,21). Nine IRFs have been identified to date, and IRF3 and its close relative IRF7 are important in controlling the induction of type I IFNs during viral infections (20,22,50). IRF7 expression is restricted to certain cell types, such as B cells and dendritic cells (DCs) (42). In other cells, IRF7 expression is inducible in response to type I IFNs as well as viral infections (42, 50). IRF7 is localized in the cytoplasm in an inactive form. Once activated, IRF7 undergoes phosphorylation and translocation to the nucleus to induce expression of the genes responsible for the production of type I IFNs (50, 53). We, and others, demonstrate...

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Section: Addition Of Exogenous Recombinant Type I Ifn Restores Cd8mentioning

confidence: 99%

Role of Interferon Regulatory Factor 7 in T Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection

Zhou

Cerny

Fitzgerald

et al. 2012

J Virol

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“…Upon stimulation of human peripheral blood mononuclear cells (PBMC) with either ConA or anti-CD3/CD28, it was found that the HCV core protein inhibited the proliferation of T lymphocytes in a dose-dependent manner (23). In addition, the production of interleukin-2 (IL-2) and IFN-␥ in cells treated with the HCV core protein was markedly diminished compared to that in control cells (12,44). Finally, several studies demonstrated that the HCV core protein may cause dysfunction in human DCs and mouse myeloid DCs in vitro (3,8,22).…”

Section: Discussionmentioning

confidence: 99%

The Wild-Type Hepatitis C Virus Core Inhibits Initiation of Antigen-Specific T- and B-Cell Immune Responses in BALB/c Mice

Zhu

Chang

et al. 2010

Clin Vaccine Immunol

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In this study, the effects of wild-type and deletion mutant hepatitis C virus (HCV) core proteins on the induction of immune responses in BALB/c mice were assessed. p2HA-C145-S23, encoding a core protein with the C-terminal 46 amino acids truncated, significantly produced stronger antibody and cellular responses than p2HA-C191-S23. The induction of immune responses by p2HA-C145-S23 was dose dependent. However, increasing the doses or repeated administration did not enhance immune responses by the wild-type core protein. In addition, p2HA-C191-S23 was apparently able to interfere with the priming of specific immune responses by p2HA-C145-S23 when the two were coadministered. These results demonstrated that the wild-type HCV core protein itself could inhibit the priming of immune responses in the course of a DNA vaccination, whereas the truncated HCV core protein could provide potential applications for the development of DNA-and peptide-based HCV vaccines.

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“…Strategies to enhance immunity should recapitulate these naturally occurring immune responses. In this regard, we and others have investigated the ability of DNA-based immunization to evoke sustained cellular immune responses against HCV antigens (6,15,16,32). Even though significant CTL activity was observed in vitro and in vivo, success was limited by a lack of memory and an overall weak CD4 ϩ T-cell response (16,27).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, we and others have investigated the ability of DNA-based immunization to evoke sustained cellular immune responses against HCV antigens (6,15,16,32). Even though significant CTL activity was observed in vitro and in vivo, success was limited by a lack of memory and an overall weak CD4 ϩ T-cell response (16,27). Notably, sustained CD4 ϩ Tcell responses appear to be a key factor in the control of HCV infection; HCV persistence, on the other hand, is related to impaired CD4 ϩ T-cell activity (39).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Generation of Immune Responses against Hepatitis C Virus by Dendritic Cells Containing NS5 Protein-Coated Microparticles

Gehring

Gregory

Wintermeyer

et al. 2009

Clin Vaccine Immunol

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Type 1 interferon augments DNA‐based vaccination against hepatitis C virus core protein

Cited by 32 publications

References 38 publications

Role of Interferon Regulatory Factor 7 in T Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection

Role of Interferon Regulatory Factor 7 in T Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection

The Wild-Type Hepatitis C Virus Core Inhibits Initiation of Antigen-Specific T- and B-Cell Immune Responses in BALB/c Mice

Generation of Immune Responses against Hepatitis C Virus by Dendritic Cells Containing NS5 Protein-Coated Microparticles

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