scholarly journals Heterologous Immunity between Adenoviruses and Hepatitis C Virus (HCV): Recombinant Adenovirus Vaccine Vectors Containing Antigens from Unrelated Pathogens Induce Cross-Reactive Immunity Against HCV Antigens

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 507 ◽  
Author(s):  
Babita Agrawal ◽  
Nancy Gupta ◽  
Satish Vedi ◽  
Shakti Singh ◽  
Wen Li ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Recombinant Adenovirus ◽  
Adenovirus Vector ◽  
Humoral Response ◽  
Positive Outcome ◽  
Cross Reactivity ◽  
Host Immune Responses

Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive immunity can (a) accommodate the making of dual-pathogen vaccines, (b) play an important role in the natural course of HCV infection and (c) provide a plausible answer to many unexplained questions regarding immunity to HCV.

scholarly journals Hepatitis C Virus Core and Envelope Proteins Do Not Suppress the Host's Ability To Clear a Hepatic Viral Infection

2001 ◽  
Vol 75 (24) ◽  
pp. 11992-11998 ◽  
Author(s):  
Jiaren Sun ◽  
Francis Bodola ◽  
Xuegong Fan ◽  
Habib Irshad ◽  
Lynn Soong ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Recombinant Adenovirus ◽  
Interleukin 2 ◽  
Envelope Proteins ◽  
Host Responses ◽  
Necrosis Factor Alpha

ABSTRACT Several hepatitis C virus (HCV) proteins have been shown in vitro to interact with host cellular components that are involved in immune regulation. However, there is a paucity of data supporting the relevance of these observations to the in vivo situation. To test the hypothesis that such an interaction suppresses immune responses, we studied a line of transgenic C57BL/6 mice that express the HCV core and envelope proteins in the liver. The potential effects of these proteins on the hepatic immune response were evaluated by challenging these mice with a hepatotropic adenovirus. Both transgenic and nontransgenic mice developed similar courses of infection and cleared the virus from the liver by 28 days postinfection. Both groups of mice mounted similar immunoglobulin G (IgG), IgG2a, interleukin-2, and tumor necrosis factor alpha responses against the virus. Additionally, BALB/c mice were able to clear infection with recombinant adenovirus that does or does not express the HCV core and envelope 1 proteins in the same manner. These data suggest that HCV core and envelope proteins do not inhibit the hepatic antiviral mechanisms in these murine experimental systems and thus favor a model in which HCV circumvents host responses through a mechanism that does not involve general suppression of intrahepatic immune responses.

scholarly journals DNA Vaccination Protects Mice against Challenge with Listeria monocytogenes Expressing the Hepatitis C Virus NS3 Protein

2003 ◽  
Vol 71 (11) ◽  
pp. 6372-6380 ◽  
Author(s):  
Benjamin E. Simon ◽  
Kenneth A. Cornell ◽  
Tina R. Clark ◽  
Sunwen Chou ◽  
Hugo R. Rosen ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Listeria Monocytogenes ◽  
Immune Responses ◽  
Bacterial Pathogen ◽  
Cell Responses ◽  
Ns3 Protein ◽  
Plasmid Dna Vaccine ◽  
In Vivo Induction

ABSTRACT The goal of this study was to develop a new surrogate challenge model for use in evaluating protective cell-mediated immune responses against hepatitis C virus (HCV) antigens. The use of recombinant Listeria monocytogenes organisms which express HCV antigens provides novel tools with which to assay such in vivo protection, as expression of immunity against this hepatotropic bacterial pathogen is dependent on antigen-specific CD8+ T lymphocytes. A plasmid DNA vaccine encoding a ubiquitin-NS3 fusion protein was generated, and its efficacy was confirmed by in vivo induction of NS3-specific, gamma interferon-secreting T cells following vaccination of BALB/c mice. These immunized mice also exhibited specific in vivo protection against subsequent challenge with a recombinant L. monocytogenes strain (TC-LNS3) expressing the NS3 protein. Notably, sublethal infection of naive mice with strain TC-LNS3 induced similar NS3-specific T-cell responses. These findings suggest that recombinant strains of L. monocytogenes expressing HCV antigens should prove useful for evaluating, or even inducing, protective immune responses against HCV antigens.

scholarly journals Involvement of Fractalkine/CX3CL1 Expression by Dendritic Cells in the Enhancement of Host Immunity against Legionella pneumophila

2005 ◽  
Vol 73 (9) ◽  
pp. 5350-5357 ◽  
Author(s):  
Toshiaki Kikuchi ◽  
Sita Andarini ◽  
Hong Xin ◽  
Kazunori Gomi ◽  
Yutaka Tokue ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Host Defense ◽  
Legionella Pneumophila ◽  
Recombinant Adenovirus ◽  
Severe Pneumonia ◽  
Adenovirus Vector ◽  
Recombinant Adenovirus Vector ◽  
Legionnaires Disease

ABSTRACT Legionnaires' disease is clinically manifested as severe pneumonia caused by Legionella pneumophila. However, the dendritic cell (DC)-centered immunological framework of the host defense against L. pneumophila has not been fully delineated. For this study, we focused on a potent chemoattractant for lymphocytes, fractalkine/CX3CL1, and observed that the fractalkine expression of DCs was somewhat up-regulated when they encountered L. pneumophila. We therefore hypothesized that fractalkine expressed by Legionella-capturing DCs is involved in the induction of T-cell-mediated immune responses against Legionella, which would be enhanced by a genetic modulation of DCs to overexpress fractalkine. In vivo immunization-challenge experiments demonstrated that DCs modified with a recombinant adenovirus vector to overexpress fractalkine (AdFKN) and pulsed with heat-killed Legionella protected immunized mice from a lethal Legionella infection and that the generation of in vivo protective immunity depended on the host lymphocyte subsets, including CD4+ T cells, CD8+ T cells, and B cells. Consistent with this, immunization with AdFKN/Legionella/DC induced significantly higher levels of serum anti-Legionella antibodies of several isotypes than those induced by control immunizations. Further analysis of spleen cells from the immunized mice indicated that the AdFKN/Legionella/DC immunization elicited Th1-dominated immune responses to L. pneumophila. These observations suggest that fractalkine may play an important role in the DC-mediated host defense against intracellular pathogens such as L. pneumophila.

scholarly journals In Vivo Study of the HC-TN Strain of Hepatitis C Virus Recovered from a Patient with Fulminant Hepatitis: RNA Transcripts of a Molecular Clone (pHC-TN) Are Infectious in Chimpanzees but Not in Huh7.5 Cells

2007 ◽  
Vol 81 (13) ◽  
pp. 7208-7219 ◽  
Author(s):  
Akito Sakai ◽  
Shingo Takikawa ◽  
Robert Thimme ◽  
Jean-Christophe Meunier ◽  
Hans Christian Spangenberg ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Disease Severity ◽  
Neutralizing Antibodies ◽  
Viral Evolution ◽  
Acute Infection ◽  
Hcv Infection ◽  
Rna Transcripts

ABSTRACT Both viral and host factors are thought to influence the pathogenesis of hepatitis C virus (HCV) infection. We studied strain HC-TN (genotype 1a), which caused fulminant hepatic failure in a patient and, subsequently, severe hepatitis in a chimpanzee (CH1422), to analyze the relationship between disease severity, host immune response, viral evolution, and outcome. A second chimpanzee (CH1581) was infected from CH1422 plasma, and a third chimpanzee (CH1579) was infected from RNA transcripts of a consensus cDNA of HC-TN (pHC-TN). RNA transcripts of pHC-TN did not replicate in Huh7.5 cells, which were recently found to be susceptible to infection with another fulminant HCV strain (JFH1). The courses of viremia were similar in the three animals. However, CH1581 and CH1579 developed a less severe acute hepatitis than CH1422. CH1579 and CH1422 resolved the infection, whereas CH1581 became persistently infected. CH1579 and CH1581, despite their differing outcomes, both developed significant intrahepatic cellular immune responses, but not antibodies to the envelope glycoproteins or neutralizing antibodies, during the acute infection. We analyzed the polyprotein sequences of virus recovered at five and nine time points from CH1579 and CH1581, respectively, during the first year of follow-up. High mutation rates and high proportions of nonsynonymous mutations suggested immune pressure and positive selection in both animals. Changes were not selected until after the initial decrease in virus titers and after the development of immune responses and hepatitis. Subsequently, however, mutations emerged repeatedly in both animals. Overall, our results indicate that disease severity and outcome of acute HCV infection depend primarily on the host response.

scholarly journals Viral and Cellular Determinants of the Hepatitis C Virus Envelope-Heparan SulfateInteraction

2006 ◽  
Vol 80 (21) ◽  
pp. 10579-10590 ◽  
Author(s):  
Heidi Barth ◽  
Eva K. Schnober ◽  
Fuming Zhang ◽  
Robert J. Linhardt ◽  
Erik Depla ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Viral Infection ◽  
Viral Envelope ◽  
Model Systems ◽  
Target Cells ◽  
Virus Envelope ◽  
Viral Attachment ◽  
Host Immune Responses

ABSTRACT Cellular binding and entry of hepatitis C virus (HCV) are the first steps of viral infection and represent a major target for antiviral antibodies and novel therapeutic strategies. We have recently demonstrated that heparan sulfate (HS) plays a key role in the binding of HCV envelope glycoprotein E2 to target cells (Barth et al., J. Biol. Chem. 278:41003-41012, 2003). In this study, we characterized the HCV-HS interaction and analyzed its inhibition by antiviral host immune responses. Using recombinant envelope glycoproteins, virus-like particles, and HCV pseudoparticles as model systems for the early steps of viral infection, we mapped viral and cellular determinants of HCV-HS interaction. HCV-HS binding required a specific HS structure that included N-sulfo groups and a minimum of 10 to 14 saccharide subunits. HCV envelope binding to HS was mediated by four viral epitopes overlapping the E2 hypervariable region 1 and E2-CD81 binding domains. In functional studies using HCV pseudoparticles, we demonstrate that HCV binding and entry are specifically inhibited by highly sulfated HS. Finally, HCV-HS binding was markedly inhibited by antiviral antibodies derived from HCV-infected individuals. In conclusion, our results demonstrate that binding of the viral envelope to a specific HS configuration represents an important step for the initiation of viral infection and is a target of antiviral host immune responses in vivo. Mapping of viral and cellular determinants of HCV-HS interaction sets the stage for the development of novel HS-based antiviral strategies targeting viral attachment and entry.

scholarly journals Heterologous Immunity and Hepatitis C Virus: Impact on Natural Infection, Pathogenesis and Vaccine Design

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 63
Author(s):  
Babita Agrawal ◽  
Shakti Singh ◽  
Nancy Gupta ◽  
Satish Vedi ◽  
Wen Li ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cells ◽  
Immune Responses ◽  
Recombinant Adenovirus ◽  
Natural Infection ◽  
Natural Immunity ◽  
Human Beings ◽  
T And B Cells ◽  
Heterologous Immunity

Chronic infection with the hepatitis C virus (HCV) afflicts 1%–3% of the world’s population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain. Host immune responses play an important role in the outcome of infection with HCV. They can lead to viral clearance and a positive outcome, or progression and severity of the chronic disease. Studies of natural immunity to HCV in humans have resulted in many enigmas. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions, implicating the role of unknown factors and events. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T and B cells. This pool of memory T and B cells can cross-react against a new pathogen in an individual and thereby influence the outcome of the new infection. In our recent studies, we made the surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses, and that immunizing mice with a non-replicating, non-recombinant adenovirus (Ad) vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. We also extended this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive/heterologous immunity can a) accommodate the development of dual-pathogen vaccines, b) play an important role in the natural course of HCV infection, and c) provide a plausible answer to many unexplained questions regarding immunity to HCV.

scholarly journals Hepatitis C Virus Structural Proteins Impair Dendritic Cell Maturation and Inhibit In Vivo Induction of Cellular Immune Responses

2003 ◽  
Vol 77 (20) ◽  
pp. 10862-10871 ◽  
Author(s):  
Pablo Sarobe ◽  
Juan José Lasarte ◽  
Aintzane Zabaleta ◽  
Laura Arribillaga ◽  
Ainhoa Arina ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cell Immunity ◽  
Cellular Immune

ABSTRACT Hepatitis C virus (HCV) chronic infection is characterized by low or undetectable cellular immune responses against HCV antigens. Some studies have suggested that HCV proteins manipulate the immune system by suppressing the specific antiviral T-cell immunity. We have previously reported that the expression of HCV core and E1 proteins (CE1) in dendritic cells (DC) impairs their ability to prime T cells in vitro. We show here that immunization of mice with immature DC transduced with an adenovirus encoding HCV core and E1 antigens (AdCE1) induced lower CD4+- and CD8+-T-cell responses than immunization with DC transduced with an adenovirus encoding NS3 (AdNS3). However, no differences in the strength of the immune response were detected when animals were immunized with mature DC subsequently transduced with AdCE1 or AdNS3. According to these findings, we observed that the expression of CE1 in DC inhibited the maturation caused by tumor necrosis factor alpha or CD40L but not that induced by lipopolysaccharide. Blockade of DC maturation by CE1 was manifested by a lower expression of maturation surface markers and was associated with a reduced ability of AdCE1-transduced DC to activate CD4+- and CD8+-T-cell responses in vivo. Our results suggest that HCV CE1 proteins modulate T-cell responses by decreasing the stimulatory ability of DC in vivo via inhibition of their physiological maturation pathways. These findings are relevant for the design of therapeutic vaccination strategies in HCV-infected patients.

scholarly journals Differential reactivity of putative genotype 2 hepatitis C virus F protein between chronic and recovered infections

2008 ◽  
Vol 89 (8) ◽  
pp. 1890-1900 ◽  
Author(s):  
Wing Chia-Ming Chuang ◽  
Jean-Pierre Allain
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Cross Reactivity ◽  
Hcv Infection ◽  
Genotype 3 ◽  
F Protein ◽  
Genotype 2

To date, all studies regarding hepatitis C virus (HCV) F protein have been based on expression in vitro/in vivo of recombinant protein or monoclonal antibodies derived from genotype 1a or 1b sequences, but not from other genotypes. The objective of this study was to prepare a putative genotype 2 recombinant F protein and evaluate its reactivity in plasma from individuals with chronic HCV infection or who had recovered from infection. One genotype 2 strain was selected for F protein (F-2) and core expression in bacterial culture. An ELISA was developed and applied to samples from patients with chronic infection or recovered infection of various genotypes. The anti-F-2 response in 117 samples showed a significantly higher reactivity in chronic than in recovered HCV-infected blood donors (P<0.001), but no difference was found among genotypes. However, the correlation between anti-F and anti-core was more significant in genotypes 1 and 2 than in genotype 3. Anti-F-2 titres were also significantly higher in chronic than in recovered individuals (P<0.0001). Antibody titres to recombinant genotype 2 core protein or to genotype 1 multiple proteins used in commercial anti-HCV assays paralleled the anti-F-2 end-point antibody titre. This study thus demonstrated the antigenicity of genotype 2 HCV F protein, although the exact location of the natural frameshift position remains unknown. The difference in anti-F-2 response between chronic and recovered infection, the cross-reactivity irrespective of genotype and the correlation of antibody response with structural and non-structural antigens suggest that the immune response to F protein is an integral part of the natural HCV infection.

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