Quantification of the number of cytotoxic T cells specific for an immunodominant HCV-specific CTL epitope primed by DNA immunization

Lee, Alexander Y.; Polakos, Noelle K.; Otten, Gillis R.; Ulmer, Jeffrey B.; Houghton, Michael; Paliard, Xavier

doi:10.1016/s0264-410x(99)00486-7

Cited by 15 publications

(11 citation statements)

References 25 publications

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“…Because of the limited knowledge of the immunogenic properties of NS5A, we sought to study its intrinsic properties. The limited number of studies of the intrinsic properties of NS5A as a genetic immunogen has demonstrated poor immunogenicity (17)(18)(19). Moreover, only a limited number of HLA-A2 CD8 + T cell-restricted epitopes have been identified (16,51,52).…”

Section: Discussionmentioning

confidence: 99%

“…The HCV NS5A is of particular interest because it is recognized by cytotoxic T lymphocytes during natural infection and resolution of acute HCV in humans (16). Thus, we decided to evaluate HCV NS5A as a therapeutic DNA vaccine candidate for chronic HCV infection, because relatively few studies have investigated NS5A as a potential vaccine (17)(18)(19). The activation of a potent antiviral T cell response is a prerequisite for a functional therapeutic vaccine in the presence of the homologous virus.…”

Section: Hronic Liver Disease Caused By the Hepatitis C Virus (Hcv)mentioning

confidence: 99%

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A Synthetic Codon-Optimized Hepatitis C Virus Nonstructural 5A DNA Vaccine Primes Polyfunctional CD8+ T Cell Responses in Wild-Type and NS5A-Transgenic Mice

Holmström

Pasetto

Nähr

et al. 2013

The Journal of Immunology

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The hepatitis C virus (HCV) nonstructural (NS) 5A protein has been shown to promote viral persistence by interfering with both innate and adaptive immunity. At the same time, the HCV NS5A protein has been suggested as a target for antiviral therapy. In this study, we performed a detailed characterization of HCV NS5A immunogenicity in wild-type (wt) and immune tolerant HCV NS5A-transgenic (Tg) C57BL/6J mice. We evaluated how efficiently HCV NS5A-based genetic vaccines could activate strong T cell responses. Truncated and full-length wt and synthetic codon-optimized NS5A genotype 1b genes were cloned into eukaryotic expression plasmids, and the immunogenicity was determined after i.m. immunization in combination with in vivo electroporation. The NS5A-based genetic vaccines primed high Ab levels, with IgG titers of >104 postimmunization. With respect to CD8+ T cell responses, the coNS5A gene primed more potent IFN-γ–producing and lytic cytotoxic T cells in wt mice compared with NS5A-Tg mice. In addition, high frequencies of NS5A-specific CD8+ T cells were found in wt mice after a single immunization. To test the functionality of the CTL responses, the ability to inhibit growth of NS5A-expressing tumor cells in vivo was analyzed after immunization. A single dose of coNS5A primed tumor-inhibiting responses in both wt and NS5A-Tg mice. Finally, immunization with the coNS5A gene primed polyfunctional NS5A-specific CD8+ T cell responses. Thus, the coNS5A gene is a promising therapeutic vaccine candidate for chronic HCV infections.

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Section: Discussionmentioning

confidence: 99%

Section: Hronic Liver Disease Caused By the Hepatitis C Virus (Hcv)mentioning

confidence: 99%

A Synthetic Codon-Optimized Hepatitis C Virus Nonstructural 5A DNA Vaccine Primes Polyfunctional CD8+ T Cell Responses in Wild-Type and NS5A-Transgenic Mice

Holmström

Pasetto

Nähr

et al. 2013

The Journal of Immunology

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“…ϩ CTLs and Th1-biased CD4 ϩ T cell responses that are the major mechanisms of protection against intracellular pathogens and tumors (7)(8)(9)(10)(11)(12). However, thus far, DNA vaccines have proved suboptimal for induction of protective immune responses in humans.…”

Section: Immunization With Rtss Induces Anti-pfcsp Abs and Cd4mentioning

confidence: 99%

Induction in Humans of CD8+ and CD4+ T Cell and Antibody Responses by Sequential Immunization with Malaria DNA and Recombinant Protein

Wang

Epstein

Charoenvit

et al. 2004

The Journal of Immunology

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Vaccine-induced protection against diseases like malaria, AIDS, and cancer may require induction of Ag-specific CD8+ and CD4+ T cell and Ab responses in the same individual. In humans, a recombinant Plasmodium falciparum circumsporozoite protein (PfCSP) candidate vaccine, RTS,S/adjuvant system number 2A (AS02A), induces T cells and Abs, but no measurable CD8+ T cells by CTL or short-term (ex vivo) IFN-γ ELISPOT assays, and partial short-term protection. P. falciparum DNA vaccines elicit CD8+ T cells by these assays, but no protection. We report that sequential immunization with a PfCSP DNA vaccine and RTS,S/AS02A induced PfCSP-specific Abs and Th1 CD4+ T cells, and CD8+ cytotoxic and Tc1 T cells. Depending upon the immunization regime, CD4+ T cells were involved in both the induction and production phases of PfCSP-specific IFN-γ responses, whereas, CD8+ T cells were involved only in the production phase. IFN-γ mRNA up-regulation was detected in both CD45RA− (CD45RO+) and CD45RA+CD4+ and CD8+ T cell populations after stimulation with PfCSP peptides. This finding suggests CD45RA+ cells function as effector T cells. The induction in humans of the three primary Ag-specific adaptive immune responses establishes a strategy for developing immunization regimens against diseases in desperate need of vaccines.

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“…C3H/HeJ mice immunized IM with D10-NS5a and boosted IM with pnewCMVII-NS5a mounted a vigorous CTL response against p214K9, a nonameric H-2 k -resticted peptide 28 located in the NS5a protein of HCV-1a (Fig. 3C).…”

Section: Construction Andmentioning

confidence: 99%

“…We (using pnewCMVII-NS5a), 28 and others, [29][30][31] have reported that intramuscular (IM) injection of ''naked'' plasmid DNA can elicit HCV-specific cellular immune responses in mice. However, T-cell-mediated immune responses primed by expressing antigens in the muscle of mice might differ from those primed when antigens are expressed primarily in the liver, as is thought to occur during HCV infection.…”

mentioning

confidence: 99%

Priming of hepatitis C virus-specific cytotoxic t lymphocytes in mice following portal vein injection of a liver-specific plasmid DNA

Lee¹,

Manning²,

Arian³

et al. 2000

Hepatology

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The immunology of hepatitis C virus (HCV) infection should be studied in the context of HCV antigen expression in the liver, because HCV primarily infects this organ. Indeed, the nature, function, and fate of T cells primed after antigen expression in the liver might differ from those primed when antigens are expressed systemically or in other organs, because the nature of the antigen-presenting cells (APCs) involved may be different. In addition, the normal liver contains a resident population of lymphocytes that differ from those present at other sites. Thus, we investigated whether HCV-specific CD8 ؉ cytotoxic T cells (CTLs) could be elicited following portal vein (PV) injection of plasmid DNA in mice whose hepatic veins were transiently occluded. We show that PV injection of mice with ''naked'' DNA expressing the HCV-NS5a protein, under the control of a liver-specific enhancer/promoter, resulted in NS5a expression in the liver and the priming of HCVspecific CTLs. These results suggested that such a model might be relevant to the study of HCV-specific immune responses primed during natural infection. (HEPATOLOGY 2000;31:1327-1333.)Hepatitis C virus (HCV), a positive-strand RNA virus member of the Flaviviridae family, 1 is recognized as a major public health concern. In addition to being one of the leading causes of chronic liver disease, 2 chronic HCV infection has been associated with autoimmune syndromes, immune complex disorders, and mixed cryoglobulinemia. 3,4 One of the most striking features of HCV is that it seems able, in most instances, to circumvent eradication by the immune system. It is estimated that up to 75% of patients infected with HCV become chronically infected, 2,5-7 despite the fact that most patients generate HCV-specific antibody, [8][9][10][11][12] as well as CD4 ϩ and CD8 ϩ T-cell responses. [13][14][15][16] On the other hand, there is evidence that humoral and T-cell-mediated immune responses to HCV infection can, at least in some instances, determine the outcome of HCV infection and disease. [17][18][19][20] In spite of recent progress in the management of chronic HCV disease, the current therapies for chronic HCV infection often do not result in viral clearance. 21,22 Thus, there is a growing interest in developing immune-based therapies for HCV. To develop such therapies, one must understand the immune responses to HCV infection, because they should provide insight into the mechanisms involved in limiting HCV replication in infected hosts. Despite the fact that substantial efforts have been made to decipher the immunology of HCV infection, it remains poorly understood. The main factors responsible for the relatively slow progress in this field are the unavailability of a small animal model for infection and disease, and inefficient systems for cultivating the virus. Because acute hepatitis in humans has been difficult to study, most attempts aimed at clarifying the immune responses to HCV have been conducted in patients with chronic hepatitis or in chimpanzees, the only reliable a...

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Quantification of the number of cytotoxic T cells specific for an immunodominant HCV-specific CTL epitope primed by DNA immunization

Cited by 15 publications

References 25 publications

A Synthetic Codon-Optimized Hepatitis C Virus Nonstructural 5A DNA Vaccine Primes Polyfunctional CD8+ T Cell Responses in Wild-Type and NS5A-Transgenic Mice

A Synthetic Codon-Optimized Hepatitis C Virus Nonstructural 5A DNA Vaccine Primes Polyfunctional CD8+ T Cell Responses in Wild-Type and NS5A-Transgenic Mice

Induction in Humans of CD8+ and CD4+ T Cell and Antibody Responses by Sequential Immunization with Malaria DNA and Recombinant Protein

Priming of hepatitis C virus-specific cytotoxic t lymphocytes in mice following portal vein injection of a liver-specific plasmid DNA

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