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1
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Bailey JT, Moshkani S, Rexhouse C, Cimino JL, Robek MD. CD4 + T cells reverse surface antigen persistence in a mouse model of HBV replication. Microbiol Spectr 2023; 11:e0344723. [PMID: 37948314 PMCID: PMC10715182 DOI: 10.1128/spectrum.03447-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 10/09/2023] [Indexed: 11/12/2023] Open
Abstract
IMPORTANCE Hepatitis B virus (HBV) is a leading causative agent of viral hepatitis. A preventative vaccine has existed for decades, but only limited treatment options are available for people living with chronic HBV. Animal models for studying HBV are constrained due to narrow viral tropism, impeding understanding of the natural immune response to the virus. Here, using a vector to overcome the narrow host range and establish HBV replication in mice, we identified the role of helper T cells in controlling HBV. We show that helper T cells promote the B cell's ability to generate antibodies that remove HBV and its associated surface antigen from the blood and that transfer of purified helper T cells from HBV-immunized mice can reverse the accumulation of virus and antigen, furthering our understanding of the immune response to HBV.
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Affiliation(s)
- Jacob T. Bailey
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Safiehkhatoon Moshkani
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Catherine Rexhouse
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Jesse L. Cimino
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Michael D. Robek
- Department of Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA
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2
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Liu J, Budylowski P, Samson R, Griffin BD, Babuadze G, Rathod B, Colwill K, Abioye JA, Schwartz JA, Law R, Yip L, Ahn SK, Chau S, Naghibosadat M, Arita Y, Hu Q, Yue FY, Banerjee A, Hardy WR, Mossman K, Mubareka S, Kozak RA, Pollanen MS, Martin Orozco N, Gingras AC, Marcusson EG, Ostrowski MA. Preclinical evaluation of a SARS-CoV-2 mRNA vaccine PTX-COVID19-B. SCIENCE ADVANCES 2022; 8:eabj9815. [PMID: 35044832 PMCID: PMC8769538 DOI: 10.1126/sciadv.abj9815] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 11/24/2021] [Indexed: 06/01/2023]
Abstract
Safe and effective vaccines are needed to end the COVID-19 pandemic. Here, we report the preclinical development of a lipid nanoparticle–formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern, including the Alpha, Beta, Gamma, and Delta lineages. No adverse effects were induced by PTX-COVID19-B in either mice or hamsters. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 2 clinical trial ongoing.
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MESH Headings
- Animals
- Antibodies, Neutralizing/blood
- Antibodies, Viral/blood
- CD4 Lymphocyte Count
- CD8-Positive T-Lymphocytes/immunology
- COVID-19/immunology
- COVID-19/prevention & control
- COVID-19 Vaccines/adverse effects
- COVID-19 Vaccines/immunology
- Canada
- Cell Line
- Cricetinae
- Drug Evaluation, Preclinical
- Female
- HEK293 Cells
- Humans
- Immunity, Cellular/immunology
- Immunity, Humoral/immunology
- Liposomes/pharmacology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Nanoparticles
- SARS-CoV-2/immunology
- Spike Glycoprotein, Coronavirus/genetics
- Spike Glycoprotein, Coronavirus/immunology
- Th1 Cells/immunology
- Vaccines, Synthetic/immunology
- mRNA Vaccines/immunology
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Affiliation(s)
- Jun Liu
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Patrick Budylowski
- Department of Medicine, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Reuben Samson
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | | | | | - Bhavisha Rathod
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | - Karen Colwill
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | | | | | - Ryan Law
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Lily Yip
- Sunnybrook Research Institute, Toronto, ON, Canada
| | - Sang Kyun Ahn
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Serena Chau
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | | | - Yuko Arita
- Providence Therapeutics Holdings Inc., Calgary, AB, Canada
| | - Queenie Hu
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | - Feng Yun Yue
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Arinjay Banerjee
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Biology, University of Waterloo, Waterloo, ON, Canada
| | - W. Rod Hardy
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | - Karen Mossman
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Samira Mubareka
- Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada
| | | | - Michael S. Pollanen
- Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada
| | | | - Anne-Claude Gingras
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
| | - Eric G. Marcusson
- Providence Therapeutics Holdings Inc., Calgary, AB, Canada
- Marcusson Consulting, San Francisco, CA, USA
| | - Mario A. Ostrowski
- Department of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
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3
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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4
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Cerino A, Mantovani S, Mele D, Oliviero B, Varchetta S, Mondelli MU. Human Monoclonal Antibodies as Adjuvant Treatment of Chronic Hepatitis B Virus Infection. Front Immunol 2019; 10:2290. [PMID: 31608071 PMCID: PMC6773823 DOI: 10.3389/fimmu.2019.02290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 09/10/2019] [Indexed: 01/05/2023] Open
Abstract
Despite the availability of an effective prophylactic vaccine leading to sterilizing immunity, hepatitis B virus (HBV) is responsible for chronic liver disease in more than 250 million individuals, potentially leading to cirrhosis and hepatocellular carcinoma. Antiviral drugs able to completely suppress virus replication are indeed available but they are, by and large, unable to eradicate the virus. Several alternative new treatment approaches are currently being developed but none have so far captured the interest of clinicians for possible clinical development. A constant feature of chronic HBV infection is T-cell exhaustion resulting from persistent exposure to high antigen concentrations as shown by the high expression of programmed cell death protein 1 (PD-1) by HBV-specific CD8 T cells. One way of tackling this problem is to develop HBV-specific neutralizing antibodies that would clear excess envelope proteins from the circulation, allowing for nucleos(t)ide analogs or other antiviral drugs now in preclinical and early clinical development to take advantage of a reconstituted adaptive immunity. Several fully human monoclonal antibodies (mAb) have been developed from HBV-vaccinated and subjects convalescent from acute hepatitis B that show different properties and specificities. It is envisaged that such neutralizing mAb may be used as adjuvant treatment to reduce viral protein load, thus rescuing adaptive immunity in an effort to optimize the effect of antiviral drugs.
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Affiliation(s)
- Antonella Cerino
- S.C. di Malattie Infettive II - Infettivologia e Immunologia, Dipartimento di Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Stefania Mantovani
- S.C. di Malattie Infettive II - Infettivologia e Immunologia, Dipartimento di Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Dalila Mele
- S.C. di Malattie Infettive II - Infettivologia e Immunologia, Dipartimento di Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Barbara Oliviero
- S.C. di Malattie Infettive II - Infettivologia e Immunologia, Dipartimento di Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Stefania Varchetta
- S.C. di Malattie Infettive II - Infettivologia e Immunologia, Dipartimento di Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mario U Mondelli
- S.C. di Malattie Infettive II - Infettivologia e Immunologia, Dipartimento di Scienze Mediche e Malattie Infettive, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Dipartimento di Medicina Interna e Terapia Medica, Università di Pavia, Pavia, Italy
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5
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Gupta PK, McIntosh CM, Chong AS, Alegre ML. The pursuit of transplantation tolerance: new mechanistic insights. Cell Mol Immunol 2019; 16:324-333. [PMID: 30760917 DOI: 10.1038/s41423-019-0203-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 01/17/2019] [Indexed: 12/11/2022] Open
Abstract
Donor-specific transplantation tolerance that enables weaning from immunosuppressive drugs but retains immune competence to non-graft antigens has been a lasting pursuit since the discovery of neonatal tolerance. More recently, efforts have been devoted not only to understanding how transplantation tolerance can be induced but also the mechanisms necessary to maintain it as well as how inflammatory exposure challenges its durability. This review focuses on recent advances regarding key peripheral mechanisms of T cell tolerance, with the underlying hypothesis that a combination of several of these mechanisms may afford a more robust and durable tolerance and that a better understanding of these individual pathways may permit longitudinal tracking of tolerance following clinical transplantation to serve as biomarkers. This review may enable a personalized assessment of the degree of tolerance in individual patients and the opportunity to strengthen the robustness of peripheral tolerance.
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Affiliation(s)
- Pawan K Gupta
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA
| | | | - Anita S Chong
- Department of Surgery, The University of Chicago, Chicago, IL, 60637, USA
| | - Maria-Luisa Alegre
- Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.
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6
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Jain S, George PJ, Deng W, Koussa J, Parkhouse K, Hensley SE, Jiang J, Lu J, Liu Z, Wei J, Zhan B, Bottazzi ME, Shen H, Lustigman S. The parasite-derived rOv-ASP-1 is an effective antigen-sparing CD4 + T cell-dependent adjuvant for the trivalent inactivated influenza vaccine, and functions in the absence of MyD88 pathway. Vaccine 2018; 36:3650-3665. [PMID: 29764680 DOI: 10.1016/j.vaccine.2018.05.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 04/26/2018] [Accepted: 05/04/2018] [Indexed: 12/18/2022]
Abstract
Vaccination remains the most cost-effective biomedical approach for controlling influenza disease. In times of pandemics, however, these vaccines cannot be produced in sufficient quantities for worldwide use by the current manufacturing capacities and practices. What is needed is the development of adjuvanted vaccines capable of inducing an adequate or better immune response at a decreased antigen dose. Previously we showed that the protein adjuvant rOv-ASP-1 augments influenza-specific antibody titers and survival after virus challenge in both young adult and old-age mice when administered with the trivalent inactivated influenza vaccine (IIV3). In this study we show that a reduced amount of rOv-ASP-1, with 40-times less IIV3 can also induce protection. Apparently the potency of the rOv-ASP-1 adjuvanted IIV3 vaccine is independent of the IIV3-specific Th1/Th2 associated antibody responses, and independent of the presence of HAI antibodies. However, CD4+ T helper cells were indispensable for the protection. Further, rOv-ASP-1 with or without IIV3 elicited the increased level of various chemokines, which are known chemoattractant for immune cells, into the muscle 4 h after immunization, and significantly induced the recruitment of monocytes, macrophages and neutrophils into the muscles. The recruited monocytes had higher expression of the activation marker MHCII on their surface as well as CXCR3 and CCR2; receptors for IP-10 and MCP-1, respectively. These results show that the rOv-ASP-1 adjuvant allows substantial antigen sparing of IIV3 by stimulating at the site of injection the accumulation of chemokines and the recruitment of immune cells that can augment the activation of CD4+ T cell immune responses, essential for the production of antibody responses. Protection elicited by the rOv-ASP-1 adjuvanted IIV3 vaccine also appears to function in the absence of MyD88-signaling. Future studies will attempt to delineate the precise mechanisms by which the rOv-ASP-1 adjuvanted IIV3 vaccine works.
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Affiliation(s)
- Sonia Jain
- Laboratory of Molecular Parasitology, Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, United States
| | - Parakkal Jovvian George
- Laboratory of Molecular Parasitology, Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, United States
| | - Wanyan Deng
- Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University, Chongqing 100045, China; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Joseph Koussa
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY 10003, United States; Department of Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Kaela Parkhouse
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Scott E Hensley
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Jiu Jiang
- Department of Biology, Drexel University, Philadelphia, PA 19104, United States
| | - Jie Lu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing 400715, China
| | - Zhuyun Liu
- Texas Children's Hospital Center for Vaccine Development, Department of Pediatric Tropical Medicine, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Junfei Wei
- Texas Children's Hospital Center for Vaccine Development, Department of Pediatric Tropical Medicine, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Bin Zhan
- Texas Children's Hospital Center for Vaccine Development, Department of Pediatric Tropical Medicine, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Maria Elena Bottazzi
- Texas Children's Hospital Center for Vaccine Development, Department of Pediatric Tropical Medicine, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Hao Shen
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Sara Lustigman
- Laboratory of Molecular Parasitology, Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10065, United States.
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7
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Lu B, Zhang B, Wang L, Ma C, Liu X, Zhao Y, Jiao Y. Hepatitis B Virus e Antigen Regulates Monocyte Function and Promotes B Lymphocyte Activation. Viral Immunol 2016; 30:35-44. [PMID: 27976981 PMCID: PMC5220529 DOI: 10.1089/vim.2016.0113] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus (HBV) e (HBe) antigen is a nonstructural virus component with great immune regulation roles. It regulates adaptive immunity response and participates in persistent infection development. However, its roles on monocytes and B lymphocytes were rarely studied. Herein, we studied HBe roles on U937 and Hmy2.CIR by creating HBe stably transfected cells using lentivirus. We detected the motility of HBe-U937 through transwell migration assay. Cytokines that primarily produced by monocytes, including BAFF, B-cell activating factor (BAFF), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and A proliferation inducing ligand (APRIL), were measured in culture supernatants of transfected U937, and serum BAFF, IL-6, and IL-10 were detected in HBe-positive and HBe-negative HBV-infected patients. Among these, BAFF mRNA and membrane-bound BAFF were further detected. Activation and inhibition markers of B lymphocytes on HBe-Hmy2.CIR and proliferation of transfected Hmy2.CIR after coculture with transfected U937 were also detected. We found that U937 migration was inhibited by HBe. BAFF expression was increased in HBe-U937, however, membrane-bound BAFF on HBe-U937 was decreased. In addition, Serum BAFF in HBe-positive patients was higher than in HBe-negative patients. IL-6 and IL-10 were increased in HBe-U937 after being stimulated by lipopolysaccharide (LPS), however, serum IL-6 and IL-10 were not associated with HBe status in patients. Besides, TNF-α and APRIL expression were basically the same in GV166-U937 and HBe-U937. B lymphocyte activation markers CD86 and Tspan33 were raised in HBe-Hmy2.CIR. However, inhibition markers Lyn and CD32b had no differences between HBe-Hmy2.CIR and control. Proliferation of transfected Hmy2.CIR was not affected by coculture with transfected U937, however, HBe transfection itself enhanced Hmy2.CIR proliferation. Altogether, these revealed that HBe can inhibit U937 migration and promote cytokines, including BAFF, IL-6, and IL-10, production in U937. Besides, HBe enhances BAFF release from U937 and increases BAFF concentration in vivo. In addition, HBe antigen facilitates Hmy2.CIR activation and proliferation through direct induction.
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Affiliation(s)
- Bingru Lu
- 1 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
| | - Bingchang Zhang
- 2 Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
| | - Laicheng Wang
- 1 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
| | - Chunyan Ma
- 1 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
| | - Xiaowen Liu
- 1 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
| | - Yueran Zhao
- 1 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
| | - Yulian Jiao
- 1 Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, People's Republic of China
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8
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Daugan M, Murira A, Mindt BC, Germain A, Tarrab E, Lapierre P, Fritz JH, Lamarre A. Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection. Front Immunol 2016; 7:564. [PMID: 27994594 PMCID: PMC5136549 DOI: 10.3389/fimmu.2016.00564] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/22/2016] [Indexed: 12/29/2022] Open
Abstract
Elicitation of type I interferon (IFN-I) has been shown to both enhance and impair cell-mediated immune responses in acute and persistent viral infections, respectively. Here, we show that, in addition to its effect on T cells, IFN-I drives impairment of specific antibody responses through interaction with B cells in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. This impairment was limited to the T cell-dependent B cell response and was associated with disruption of B cell follicles, development of hypergammaglobulinemia (HGG), and expansion of the T follicular helper cell population. Antigen-specific antibody responses were restored by ablation of IFN-I signaling through antibody-mediated IFN-I receptor blockade and B cell-specific IFN-I receptor knockout. Importantly, IFN-I receptor deficiency in B cells also accelerated the development of LCMV neutralizing antibodies and alleviated HGG. These results provide a potential therapeutic target toward efficient treatment measures that limit immunopathology in persistent viral infections.
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Affiliation(s)
- Matthieu Daugan
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, QC, Canada
| | - Armstrong Murira
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, QC, Canada
| | - Barbara C. Mindt
- Complex Traits Group, Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
| | - Amélie Germain
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, QC, Canada
| | - Esther Tarrab
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, QC, Canada
| | - Pascal Lapierre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, QC, Canada
| | - Jörg H. Fritz
- Complex Traits Group, Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Complex Traits Group, Department of Physiology, McGill University, Montréal, QC, Canada
| | - Alain Lamarre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, QC, Canada
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9
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Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: A growing relationship. Cell Immunol 2016; 310:27-41. [PMID: 27660198 DOI: 10.1016/j.cellimm.2016.09.009] [Citation(s) in RCA: 217] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/14/2016] [Accepted: 09/15/2016] [Indexed: 12/20/2022]
Abstract
Programmed death 1 (PD-1) and its ligands, namely PD-L1 and PD-L2, are one of the key factors responsible for inhibitory T cell signaling, mediating the mechanisms of tolerance and providing immune homeostasis. Mounting evidence demonstrates that impaired PD-1:PD-L function plays an important role in a variety of autoimmune diseases such as Type 1 diabetes (T1D), encephalomyelitis, inflammatory bowel diseases (IBD), Rheumatoid Arthritis (RA), autoimmune hepatitis (AIH), Behcet's disease (BD), myasthenia gravis (MG), autoimmune uveitis (AU), Sjögren's syndrome (SjS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), myocarditis, and ankylosing spondylitis (AS). By investigating the candidate genes, genome-wide association studies, and identification of single nucleotide polymorphisms (SNPs) in PD-1 gene in humans, it has been shown that there is a higher risk in relevant genetic associations with developing autoimmune diseases in certain ethnic groups. In this review we have tried to present a comprehensive role of PD-1:PD-L in all recently studied autoimmune diseases.
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Affiliation(s)
- Mohammad Reza Zamani
- Department of Immunology and Biology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Saeed Aslani
- Department of Immunology and Biology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Salmaninejad
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Javan
- Department of Immunology, Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Nima Rezaei
- Department of Immunology and Biology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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10
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Clouthier DL, Watts TH. TNFRs and Control of Chronic LCMV Infection: Implications for Therapy. Trends Immunol 2015; 36:697-708. [PMID: 26481667 DOI: 10.1016/j.it.2015.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 09/08/2015] [Accepted: 09/15/2015] [Indexed: 12/11/2022]
Abstract
The control of persistent viral infections requires the immune system to limit the spread of the virus while avoiding immunopathology. Recent studies have revealed that members of the tumor necrosis factor receptor (TNFR) superfamily play unique and pivotal roles in control of chronic lymphocytic choriomeningitis virus (LCMV) infection and in some settings can tip the balance between immune control and immune pathology. We review these findings and discuss how our understanding of the role of TNFRs in the immune response to chronic LCMV infection may shed light on what happens during HIV infection in humans. We discuss preclinical models of TNF/TNFR family-targeted immunotherapy of chronic LCMV infection and evaluate which TNFRs present the most promising targets for immune intervention.
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Affiliation(s)
- Derek L Clouthier
- Department of Immunology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada
| | - Tania H Watts
- Department of Immunology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
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11
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Early preservation of CXCR5+ PD-1+ helper T cells and B cell activation predict the breadth of neutralizing antibody responses in chronic HIV-1 infection. J Virol 2014; 88:13310-21. [PMID: 25210168 DOI: 10.1128/jvi.02186-14] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Much is known about the characteristics of broadly neutralizing antibodies (bNAbs) generated during HIV-1 infection, but little is known about immunological mechanisms responsible for their development in only a minority of those infected by HIV-1. By monitoring longitudinally a cohort of HIV-1-infected subjects, we observed that the preservation of CXCR5(+) CD4(+) T helper cell frequencies and activation status of B cells during the first year of infection correlates with the maximum breadth of plasma neutralizing antibody responses during chronic infection independently of viral load. Although, during the first year of infection, no differences were observed in the abilities of peripheral CXCR5(+) CD4(+) T helper cells to induce antibody secretion by autologous naive B cells, higher frequencies of class-switched antibodies were detected in cocultures of CXCR5(+) CD4(+) T and B cells from the subjects who later developed broadly neutralizing antibody responses than those who did not. Furthermore, B cells from the former subjects had higher expression of AICDA than B cells from the latter subjects, and transcript levels correlated with the frequency of CXCR5(+) CD4(+) T cells. Thus, the early preservation of CXCR5(+) CD4(+) T cells and B cell function are central to the development of bNAbs. Our study provides a possible explanation for their infrequent generation during HIV-1 infection. IMPORTANCE Broadly neutralizing antibodies are developed by HIV-1-infected subjects, but so far (and despite intensive efforts over the past 3 decades) they have not been elicited by immunization. Understanding how bNAbs are generated during natural HIV-1 infection and why only some HIV-1-infected subjects generate such antibodies will assist our efforts to elicit bNAbs by immunization. CXCR5(+) PD-1(+) CD4(+) T cells are critical for the development of high-affinity antigen-specific antibody responses. In our study, we found that the HIV-1-infected subjects who develop bNAbs have a higher frequency of peripheral CXCR5(+) PD-1(+) CD4(+) T cells in early infection and also that this frequency mirrored what was observed in uninfected subjects and correlated with the level of B cell activation across subjects. Our study highlights the critical role helper T cell function has in the elicitation of broadly neutralizing antibody responses in the context of HIV infection.
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Perez-Shibayama C, Gil-Cruz C, Ludewig B. Plasticity and complexity of B cell responses against persisting pathogens. Immunol Lett 2014; 162:53-8. [PMID: 25068435 DOI: 10.1016/j.imlet.2014.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/09/2014] [Accepted: 07/17/2014] [Indexed: 11/29/2022]
Abstract
Vaccines against acute infections execute their protective effects almost exclusively via the induction of antibodies. Development of protective vaccines against persisting pathogens lags behind probably because standard immunogens and application regimen do not sufficiently stimulate those circuits in B cell activation that mediate protection. In general, B cell responses against pathogen derived-antigens are generated through complex cellular interactions requiring the coordination of innate and adaptive immune mechanisms. In this review, we summarize recent findings from prototypic infection models to exemplify how generation of protective antibodies against persisting pathogens is imprinted by particular pathogen-derived factors and how distinct CD4(+) T cell populations determine the quality of these antibodies. Clearly, it is the high plasticity of these processes that is instrumental to drive tailored B cell responses that protect the host. In sum, application of novel knowledge on B cell plasticity and complexity can guide the development of rationally designed vaccines that elicit protective antibodies against persisting pathogens.
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Affiliation(s)
- Christian Perez-Shibayama
- Institute of Immunobiology, Kantonsspital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
| | - Cristina Gil-Cruz
- Institute of Immunobiology, Kantonsspital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonsspital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland.
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13
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Walton S, Mandaric S, Oxenius A. CD4 T cell responses in latent and chronic viral infections. Front Immunol 2013; 4:105. [PMID: 23717308 PMCID: PMC3651995 DOI: 10.3389/fimmu.2013.00105] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 04/22/2013] [Indexed: 12/24/2022] Open
Abstract
The spectrum of tasks which is fulfilled by CD4 T cells in the setting of viral infections is large, ranging from support of CD8 T cells and humoral immunity to exertion of direct antiviral effector functions. While our knowledge about the differentiation pathways, plasticity, and memory of CD4 T cell responses upon acute infections or immunizations has significantly increased during the past years, much less is still known about CD4 T cell differentiation and their beneficial or pathological functions during persistent viral infections. In this review we summarize current knowledge about the differentiation, direct or indirect antiviral effector functions, and the regulation of virus-specific CD4 T cells in the setting of persistent latent or active chronic viral infections with a particular emphasis on herpes virus infections for the former and chronic lymphocytic choriomeningitis virus infection for the latter.
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Affiliation(s)
- Senta Walton
- Department of Microbiology and Immunology, School of Pathology and Laboratory Medicine, University of Western Australia Nedlands, WA, Australia
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14
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Boyd A, Girard PM, Lacombe K. Consequences of persistent HBV infection in HIV: the double-edged sword of nucleos(t)ide analogs. Future Virol 2012. [DOI: 10.2217/fvl.11.144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A variety of nucleos(t)ide analogs (NA) are available to treat HBV infection, the majority of which are also active against HIV, and when alone or in combination, have proven to actively suppress circulating HBV. However during treatment, especially among HIV-infected patients, the persistent nature of replicating intracellular DNA and lack of HBsAg loss indicates the potential for NA resistance and hence changes in HBV genetic variability. Meanwhile, cytotoxic CD8+ T cells responsible for clearing infected hepatocytes appear to become exhausted and anti-HBV immunoglobulin-producing B cells become deficient; both of which can be altered during HIV infection. Furthermore, host-determinants, specifically regulation of HBV integration into the host genome and polymorphisms on the HLA allele, have been shown to affect HBV replication. Studies on how these selective pressures influence HBV genetic variability are sparse, yet lead to important considerations on NA resistance during persistent infection.
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Affiliation(s)
- Anders Boyd
- Hôpital Saint-Antoine, Services des Maladies Infectieuses et Tropicales, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
| | - Pierre-Marie Girard
- Hôpital Saint-Antoine, Services des Maladies Infectieuses et Tropicales, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
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15
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Matter MS, Hilmenyuk T, Claus C, Marone R, Schürch C, Tinguely M, Terracciano L, Luther SA, Ochsenbein AF. Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells. PLoS One 2011; 6:e24772. [PMID: 21966366 PMCID: PMC3179489 DOI: 10.1371/journal.pone.0024772] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Accepted: 08/17/2011] [Indexed: 11/19/2022] Open
Abstract
Immune responses have the important function of host defense and protection against pathogens. However, the immune response also causes inflammation and host tissue injury, termed immunopathology. For example, hepatitis B and C virus infection in humans cause immunopathological sequel with destruction of liver cells by the host's own immune response. Similarly, after infection with lymphocytic choriomeningitis virus (LCMV) in mice, the adaptive immune response causes liver cell damage, choriomeningitis and destruction of lymphoid organ architecture. The immunopathological sequel during LCMV infection has been attributed to cytotoxic CD8(+) T cells. However, we now show that during LCMV infection CD4(+) T cells selectively induced the destruction of splenic marginal zone and caused liver cell damage with elevated serum alanin-transferase (ALT) levels. The destruction of the splenic marginal zone by CD4(+) T cells included the reduction of marginal zone B cells, marginal zone macrophages and marginal zone metallophilic macrophages. Functionally, this resulted in an impaired production of neutralizing antibodies against LCMV. Furthermore, CD4(+) T cells reduced B cells with an IgM(high)IgD(low) phenotype (transitional stage 1 and 2, marginal zone B cells), whereas other B cell subtypes such as follicular type 1 and 2 and germinal center/memory B cells were not affected. Adoptive transfer of CD4(+) T cells lacking different important effector cytokines and cytolytic pathways such as IFNγ, TNFα, perforin and Fas-FasL interaction did reveal that these cytolytic pathways are redundant in the induction of immunopathological sequel in spleen. In conclusion, our results define an important role of CD4(+) T cells in the induction of immunopathology in liver and spleen. This includes the CD4(+) T cell mediated destruction of the splenic marginal zone with consecutively impaired protective neutralizing antibody responses.
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MESH Headings
- Adoptive Transfer
- Animals
- Antibodies, Neutralizing/immunology
- Antibodies, Neutralizing/metabolism
- Antibodies, Viral/immunology
- Antibodies, Viral/metabolism
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Chemokines/genetics
- Chemokines/immunology
- Chemokines/metabolism
- Fas Ligand Protein/deficiency
- Fas Ligand Protein/genetics
- Fas Ligand Protein/immunology
- Flow Cytometry
- Hepatitis, Viral, Animal/immunology
- Hepatitis, Viral, Animal/metabolism
- Hepatitis, Viral, Animal/virology
- Interferon-gamma/deficiency
- Interferon-gamma/genetics
- Interferon-gamma/immunology
- Lymphocytic Choriomeningitis/immunology
- Lymphocytic Choriomeningitis/metabolism
- Lymphocytic choriomeningitis virus/immunology
- Lymphoid Tissue/immunology
- Lymphoid Tissue/metabolism
- Lymphoid Tissue/virology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Microscopy, Fluorescence
- Perforin/deficiency
- Perforin/genetics
- Perforin/immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Spleen/immunology
- Spleen/metabolism
- Spleen/virology
- Time Factors
- Tumor Necrosis Factor-alpha/deficiency
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/immunology
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Affiliation(s)
- Matthias S Matter
- Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland.
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16
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Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. ACTA ACUST UNITED AC 2011; 208:987-99. [PMID: 21536743 PMCID: PMC3092345 DOI: 10.1084/jem.20101773] [Citation(s) in RCA: 271] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Persistent virus infection drives follicular T helper cell differentiation. CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.
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Affiliation(s)
- Laura M Fahey
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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17
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Hashem M, El-Karaksy H, Shata MT, Sobhy M, Helmy H, El-Naghi S, Galal G, Ali ZZ, Esmat G, Abdelwahab SF, Strickland GT, El-Kamary SS. Strong hepatitis C virus (HCV)-specific cell-mediated immune responses in the absence of viremia or antibodies among uninfected siblings of HCV chronically infected children. J Infect Dis 2011; 203:854-861. [PMID: 21257736 PMCID: PMC3071132 DOI: 10.1093/infdis/jiq123] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Accepted: 10/29/2010] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cell-mediated immune (CMI) responses to hepatitis C virus (HCV) antigens in adults without seroconversion or viremia are biomarkers for prior transient infection. We investigated HCV-specific CMI responses in seronegative children living with HCV-infected siblings. METHODS Children 3-18 years of age living with HCV-infected siblings were screened for HCV antibodies and HCV RNA. Peripheral blood mononuclear cells (PBMCs) were evaluated for HCV-specific CMI responses by interferon γ (IFN-γ) enzyme-linked immunospot assay using 3 recombinant HCV protein antigens. Flow cytometry phenotypically characterized IFN-γ-secreting cells. RESULTS Forty-five seronegative children and 5 seropositive viremic siblings had functionally viable PBMCs. Among the 45 seronegative siblings, 15 (33.3%) had positive HCV-specific IFN-γ responses, and subsequent RNA testing revealed that 3 were viremic. Compared with the 5 seropositive viremic children, the median number of HCV-specific spot-forming units was significantly higher in the 12 seronegative aviremic children (P = .002) and in the 3 seronegative viremic children (P = .025). Flow cytometric analysis revealed that IFN-γ was synthesized mainly by CD4(+) T cells. CONCLUSION Strong HCV-specific CD4(+) T cell responses were detectable in higher frequency among seronegative, aviremic children compared with persistently infected siblings. Further studies are needed to determine whether these immune responses are protective against HCV infection.
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Affiliation(s)
- Mohamed Hashem
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
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18
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Modeling the adaptive immune response in HBV infection. J Math Biol 2011; 63:933-57. [PMID: 21234570 DOI: 10.1007/s00285-010-0397-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2009] [Revised: 12/20/2010] [Indexed: 12/31/2022]
Abstract
The aim of this work is to investigate a new mathematical model that describes the interactions between Hepatitis B virus (HBV), liver cells (hepatocytes), and the adaptive immune response. The qualitative analysis of this as cytotoxic T lymphocytes (CTL) cells and the antibodies. These outcomes are (1) a disease free steady state, which its local stability is characterized as usual by R (0) < 1, (2) and the existence of four endemic steady states when R (0) > 1. The local stability of these steady states depends on functions of R (0). Our study shows that although we give conditions of stability of these steady states, not all conditions are feasible. This rules out the local stability of two steady states. The conditions of stability of the two other steady states (which represent the complete failure of the adaptive immunity and the persistence of the disease) are formulated based on the domination of CTL cells response or the antibody response.
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19
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Ferrari C, Mondelli M. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2009:835-857. [DOI: 10.1002/9780470747919.ch51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Carambia A, Herkel J. CD4 T cells in hepatic immune tolerance. J Autoimmun 2009; 34:23-8. [PMID: 19720498 DOI: 10.1016/j.jaut.2009.08.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Accepted: 08/13/2009] [Indexed: 12/20/2022]
Abstract
The liver features a unique immune microenvironment, which seems to favour immune tolerance, both locally and systemically. The hepatic microenvironment is formed by the unique anatomical structure of the liver sinusoids, a peculiar composition of antigen presenting cells and the relative abundance of anti-inflammatory cytokines. The outcome of T cell stimulation within the hepatic microenvironment is often tolerance. This is illustrated by the observations that antigen delivered to the portal vein, or allografts co-transplanted with allogeneic liver are not attacked by the immune system. Moreover, the tolerogenic properties of the liver seem to be part of the cause for the frequent persistence of hepatitis virus infections. This review summarizes some of the mechanisms of tolerance induction in the liver with a focus on CD4 T cells. Hepatic CD4 T cell tolerance seems to emerge from various tolerogenic mechanisms, including immune deviation from inflammatory to non-inflammatory effector function, a relative preponderance of negative co-stimulation notably through PD-1, generation and expansion of regulatory T cells, or the relative abundance of immunoinhibitory cytokines, such as inteleukin-10 and TGF-beta. Understanding the mechanisms of hepatic tolerance induction may teach us how to develop or improve therapies for inflammatory diseases of the liver and other organs. Indeed, novel therapeutic options that utilize hepatic tolerance mechanisms are beginning to emerge, such as the generation of Treg in the liver for therapy of autoimmune disease or the blockade of PD-1 for the therapy of chronic viral hepatitis.
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Affiliation(s)
- Antonella Carambia
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
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21
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Tan AT, Koh S, Goh V, Bertoletti A. Understanding the immunopathogenesis of chronic hepatitis B virus: an Asian prospective. J Gastroenterol Hepatol 2008; 23:833-43. [PMID: 18565018 DOI: 10.1111/j.1440-1746.2008.05385.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The study of hepatitis B virus (HBV) immunity has been mainly focused on understanding the differences between subjects who are able to control HBV infection and patients with persistent infection. These studies have been instrumental in increasing our knowledge on the pathogenesis of the disease caused by HBV. However, it is possible that heterogeneity of host and virus factors which segregate in ethnically distinct HBV infected populations might modify important aspects of the immune response against HBV. In this review, we reexamine the kinetics and the pattern of HBV-specific immunity associated with control or persistence of infection. We then discuss how the epidemiological, genetic and viral characteristics peculiar to Asian patients can impact the profile of HBV-specific immunity.
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Affiliation(s)
- Anthony Tanoto Tan
- Viral Hepatitis Unit, Singapore Institute for Clinical Science, A*STAR, Singapore
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22
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Li H, Chien PC, Tuen M, Visciano ML, Cohen S, Blais S, Xu CF, Zhang HT, Hioe CE. Identification of an N-linked glycosylation in the C4 region of HIV-1 envelope gp120 that is critical for recognition of neighboring CD4 T cell epitopes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 180:4011-21. [PMID: 18322210 DOI: 10.4049/jimmunol.180.6.4011] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The heavy glycosylation of HIV-1 envelope gp120 shields this important Ag from recognition by neutralizing Abs and cytolytic CD8 T cells. However, very little work has been done to understand the influence of glycosylation on the generation of gp120 epitopes and their recognition by MHC class II-restricted CD4 T cells. In this study, three conserved glycans (linked to N406, N448, and N463) flanking the C4 region of gp120 that contains many known CD4 T cell epitopes were disrupted individually or in combination by asparagine-to-glutamine substitutions. The mutant proteins lacking the N448 glycan did not effectively stimulate CD4 T cells specific for the nearby C4 epitopes, although the same mutants were recognized well by CD4 T cells specific for epitopes located in the distant C1 and C2 regions. The loss of recognition was not due to amino acid substitutions introduced to the mutant proteins. Data from trypsin digestion and mass spectrometry analyses demonstrated that the N448 glycan removal impeded the proteolytic cleavage of the nearby C4 region, without affecting more distant sites. Importantly, this inhibitory effect was observed only in the digestion of the native nondenatured protein and not in that of the denatured protein. These data indicate that the loss of the N448 glycan induces structural changes in the C4 region of gp120 that make this specific region more resistant to proteolytic processing, thereby restricting the generation of CD4 T cell epitopes from this region. Hence, N-linked glycans are critical determinants that can profoundly influence CD4 T cell recognition of HIV-1 gp120.
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Affiliation(s)
- Hualin Li
- Department of Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA
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23
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You J, Sriplung H, Geater A, Chongsuvivatwong V, Zhuang L, Chen HY, Yu L, Tang BZ, Huang JH. Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B. World J Gastroenterol 2008; 14:1112-9. [PMID: 18286696 PMCID: PMC2689417 DOI: 10.3748/wjg.14.1112] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 10/23/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate peripheral T-lymphocyte sub-population profile and its correlation with hepatitis B virus (HBV) replication in patients with chronic hepatitis B (CHB). METHODS Distribution of T-lymphocyte subpopulations in peripheral blood was measured by flow cytometry in 206 CHB patients. HBV markers were detected with ELISA. Serum HBV DNA load was assessed with quantitative real-time polymerase chain reaction (PCR). The relationship between HBV replication and variation in peripheral T-cell subsets was analyzed. RESULTS CHB patients had significantly decreased CD3+ and CD4+ cells and CD4+/CD8+ ratio, and increased CD8+ cells compared with uninfected controls (55.44 +/- 12.39 vs 71.07 +/- 4.76, 30.92 +/- 7.48 vs 38.94 +/- 3.39, 1.01 +/- 0.49 vs 1.67 +/- 0.33, and 34.39 +/- 9.22 vs 24.02 +/- 4.35; P < 0.001, respectively). Univariate analysis showed a similar pattern of these parameters was significantly associated with high viral load, presence of serum hepatitis B e antigen (HBeAg) expression, liver disease severity, history of maternal HBV infection, and young age at HBV infection, all with P < 0.01. There was a significant linear relationship between viral load and these parameters of T-lymphocyte subpopulations (linear trend test P < 0.001). There was a negative correlation between the levels of CD3+ and CD4+ cells and CD4+/CD8+ ratio and serum level of viral load in CHB patients (r = -0.68, -0.65 and -0.75, all P < 0.0001), and a positive correlation between CD8+ cells and viral load (r = 0.70, P < 0.0001). There was a significant decreasing trend in CD3+ and CD4+ cells and CD4+/CD8+ ratio with increasing severity of hepatocyte damage and decreasing age at HBV infection (linear trend test P < 0.01). In multiple regression (after adjustment for age at HBV infection, maternal HBV infection status and hepatocyte damage severity) log copies of HBV DNA maintained a highly significant predictive coefficient on T-lymphocyte subpopulations, and was the strongest predictor of variation in CD3+, CD4+, CD8+ cells and CD4+/CD8+ ratio. However, the effect of HBeAg was not significant. CONCLUSION T-lymphocyte failure was significantly associated with viral replication level. The substantial linear dose-response relationship and strong independent predictive effect of viral load on T-lymphocyte subpopulations suggests the possibility of a causal relationship between them, and indicates the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients.
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Abstract
Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are relatively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type I profile, which promotes cellular effector mechanisms are thought to be more likely to experience viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells, especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in determining the outcome of acute and chronic HCV infection will be discussed in this review.
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Affiliation(s)
- Nasser Semmo
- Nuffield Department of Clinical Medicine, University of Oxford, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom
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Zimmermann VS, Casati A, Schiering C, Caserta S, Hess Michelini R, Basso V, Mondino A. Tumors Hamper the Immunogenic Competence of CD4+T Cell-Directed Dendritic Cell Vaccination. THE JOURNAL OF IMMUNOLOGY 2007; 179:2899-909. [PMID: 17709504 DOI: 10.4049/jimmunol.179.5.2899] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Dendritic cells loaded with tumor-derived peptides induce protective CTL responses and are under evaluation in clinical trails. We report in this study that prophylactic administration of dendritic cells loaded with a MHC class II-restricted peptide derived from a model tumor Ag (Leishmania receptor for activated C kinase (LACK)) confers protection against LACK-expressing TS/A tumors, whereas therapeutic vaccination fails to cure tumor-bearing mice. Although CD4+ T cell-directed dendritic cell vaccination primed effector-like (CD44(high)CD62L(low), IL-2(+), IFN-gamma(+)) and central memory-like lymphocytes (CD44(high)CD62L(high), only IL-2(+)) in tumor-free mice, this was not the case in tumor-bearing animals in which both priming and persistence of CD4+ T cell memory were suppressed. Suppression was specific for the tumor-associated Ag LACK, and did not depend on CD25+ T cells. Because T cell help is needed for protective immunity, we speculate that the ability of tumors to limit vaccine-induced CD4+ T cell memory could provide a partial explanation for the limited efficacy of current strategies.
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Affiliation(s)
- Valérie S Zimmermann
- Cancer Immunotherapy and Gene Therapy Program, Department of Biotechnology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy
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Eschli B, Zellweger RM, Wepf A, Lang KS, Quirin K, Weber J, Zinkernagel RM, Hengartner H. Early antibodies specific for the neutralizing epitope on the receptor binding subunit of the lymphocytic choriomeningitis virus glycoprotein fail to neutralize the virus. J Virol 2007; 81:11650-7. [PMID: 17699567 PMCID: PMC2168768 DOI: 10.1128/jvi.00955-07] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Lymphocytic choriomeningitis virus (LCMV) is a murine arenavirus whose glycoprotein consists of a transmembrane subunit (GP-2) and a receptor-binding subunit (GP-1). LCMV-neutralizing antibodies (nAbs) are directed against a single site on GP-1 and occur 1 month after the infection of cytotoxic-T-lymphocyte (CTL) deficient mice. In wild-type mice, however, CTLs control early infection, and weak nAb titers emerge very late (after 70 to 150 days) if at all. Production of recombinant GP-1 in native conformation enabled us to study the emergence of GP-1-binding antibodies directed against the neutralizing epitope. By combining binding and neutralization assays, we correlated the development of binding antibodies versus nAbs in wild-type and CTL-deficient mice after infection with different LCMV doses. We found that wild-type mice developed GP-1-specific antibodies already by day 8 after exposure to high but not low doses, demonstrating that naive GP-1-specific B cells were infrequent. Furthermore, the induced antibodies bound to the neutralizing GP-1 epitope but failed to neutralize the virus and therefore were of low affinity. In CTL-deficient mice, where massive viremia quickly levels initial differences in viral load, low and high doses induced low-affinity non-neutralizing GP-1-binding antibodies with kinetics similar to high-dose-infected wild-type mice. Only in CTL-deficient mice, however, the GP-1-specific antibodies developed into nAbs within 1 month. We conclude that LCMV uses a dual strategy to evade nAb responses in wild-type mice. First, LCMV exploits a "hole" in the murine B-cell repertoire, which provides only a small and narrow initial pool of low-affinity GP-1-specific B cells. Second, affinity maturation of the available low-affinity non-neutralizing antibodies is impaired.
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Affiliation(s)
- Bruno Eschli
- Institute of Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
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27
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Semmo N, Krashias G, Willberg C, Klenerman P. Analysis of the relationship between cytokine secretion and proliferative capacity in hepatitis C virus infection. J Viral Hepat 2007; 14:492-502. [PMID: 17576391 DOI: 10.1111/j.1365-2893.2007.00842.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CD4(+) T-cell responses are important for the outcome of hepatitis C virus (HCV) infection. However, the functional status of HCV-specific CD4(+) T cells in persistent infection is poorly understood. It is generally recognized that proliferative capacity of HCV-specific CD4(+) T cells is weak or absent in persistent infection, but whether this results from deletion of antigen-specific cells or represents maintenance of antigen-specific but poorly proliferative populations is not defined. We used a set of ex vivo assays to evaluate the functionality of HCV specific CD4(+) T cells in persistent and resolved infection. Peripheral blood mononuclear cells (PBMC) from 24 prospectively recruited HCV polymerase chain reaction (PCR) positive individuals, 12 spontaneously resolved individuals (i.e. anti-HCV+, PCR-) and 11 healthy controls were analysed for interferon-gamma (IFN-gamma) and interleukin 2 (IL-2) secretion by enzyme linked immunospot assays (ELISpot). HCV-specific CD4(+) proliferative responses of carboxy fluorescein succinimidyl ester-labelled PBMC were assessed using a sensitive single cell flow cytometric assay. Sustained IFN-gamma ELISpot responses were observed in the PCR+ group. However, proliferation of HCV-specific CD4(+) T cells in the PCR+ group was substantially reduced on a per cell basis, in parallel to IL-2 secretion, compared with responses in the PCR- group. In PCR- individuals, a strong relationship between cytokine secretion and proliferative capacity was seen. However, in PCR+ individuals, IFN-gamma secretion far exceeded proliferative capacity. During persistent HCV infection, some CD4(+) T-cell specificities appear to be lost, as measured using a range of techniques, but others, potentially important, are maintained as IFN-gamma secretors but with low proliferative capacity even using a highly sensitive assay. Such subsets may yet play a significant role in vivo and also provide a template for modulation in immunotherapeutic interventions.
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Affiliation(s)
- N Semmo
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
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28
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Singh NJ, Chen C, Schwartz RH. The impact of T cell intrinsic antigen adaptation on peripheral immune tolerance. PLoS Biol 2007; 4:e340. [PMID: 17048986 PMCID: PMC1609129 DOI: 10.1371/journal.pbio.0040340] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Accepted: 08/16/2006] [Indexed: 11/19/2022] Open
Abstract
Overlapping roles have been ascribed for T cell anergy, clonal deletion, and regulation in the maintenance of peripheral immunological tolerance. A measurement of the individual and additive impacts of each of these processes on systemic tolerance is often lacking. In this report we have used adoptive transfer strategies to tease out the unique contribution of T cell intrinsic receptor calibration (adaptation) in the maintenance of tolerance to a systemic self-antigen. Adoptively transferred naïve T cells stably calibrated their responsiveness to a persistent self-antigen in both lymphopenic and T cell-replete hosts. In the former, this state was not accompanied by deletion or suppression, allowing us to examine the unique contribution of adaptation to systemic tolerance. Surprisingly, adapting T cells could chronically help antigen-expressing B cells, leading to polyclonal hypergammaglobulinemia and pathology, in the form of mild arthritis. The helper activity mediated by CD40L and cytokines was evident even if the B cells were introduced after extended adaptation of the T cells. In contrast, in the T cell-replete host, neither arthritis nor autoantibodies were induced. The containment of systemic pathology required host T cell-mediated extrinsic regulatory mechanisms to synergize with the cell intrinsic adaptation process. These extrinsic mechanisms prevented the effector differentiation of the autoreactive T cells and reduced their precursor frequency, in vivo.
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Affiliation(s)
- Nevil J Singh
- Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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29
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Charalambous A, Oks M, Nchinda G, Yamazaki S, Steinman RM. Dendritic cell targeting of survivin protein in a xenogeneic form elicits strong CD4+ T cell immunity to mouse survivin. THE JOURNAL OF IMMUNOLOGY 2007; 177:8410-21. [PMID: 17142738 DOI: 10.4049/jimmunol.177.12.8410] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
To determine whether strong CD4+ T cell immunity could be induced to a nonmutated self protein that is important for tumorigenesis, we selectively targeted the xenogeneic form of survivin, a survival protein overexpressed in tumors, to maturing dendritic cells in lymphoid tissues. Dendritic cell targeting via the DEC205 receptor in the presence of anti-CD40 and poly(I:C) as maturation stimuli, induced strong human and mouse survivin-specific CD4+ T cell responses, as determined by IFN-gamma, TNF-alpha, and IL-2 production, as well as the development of lytic MHC class II-restricted T cells and memory. Immunity was enhanced further by depletion of CD25+foxp3+ cells before vaccination. anti-DEC205-human survivin was superior in inducing CD4+ T cell responses relative to other approaches involving survivin plasmid DNA or survivin peptides with adjuvants. However, we were unable to induce CD8+ T cell immunity to survivin by two doses of DEC205-targeted survivin or the other strategies. Therefore, significant CD4+ T cell immunity to a self protein that is overexpressed in most human cancers can be induced by DEC205 targeting of the Ag in its xenogeneic form to maturing DCs.
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Affiliation(s)
- Anna Charalambous
- Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
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30
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Desombere I, Van Vlierberghe H, Weiland O, Hultgren C, Sällberg M, Quiroga J, Carreño V, Leroux-Roels G. Serum levels of anti-NS4a and anti-NS5a predict treatment response of patients with chronic hepatitis C. J Med Virol 2007; 79:701-13. [PMID: 17457916 DOI: 10.1002/jmv.20846] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In order to understand better the clinical significance and prognostic value of antibody responses to HCV proteins and in search for parameters that may allow the early identification of non-sustained responders to therapy, antibody levels were measured against NS3, NS4a and NS5a at baseline in the serum of 120 patients chronically infected with HCV of genotype 1 that were classified as sustained responders, relapsers, or non-responders to therapy. The capacity of these antibody tests to predict therapy-outcome was evaluated. While no differences were observed in the anti-NS3 responses in these different response groups, anti-NS4a and anti-NS5a antibodies were observed more frequently and at higher titres in sustained responders versus non-responders or non-sustained responders (=non-responders + relapsers). Based on this observation, a combination of test results consisting of 'the absence of NS4a (AA 1687-1718) antibody at baseline and the presence of HCV-RNA exceeding 10(5) IU/ml after 1 week of treatment' was identified which predicts non-sustained response to treatment with 100% certainty. Replacing the HCV-RNA decision limit by a HCV-core antigen level of >15 pg/ml resulted in the same predictive value. The proposed algorithm also holds for patients treated with peg-interferon and ribavirin. In conclusion, in patients with chronic HCV infection, the decision to continue or stop treatment can be made after 1 week of treatment with (peg)-interferon alpha and ribavirin.
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31
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Ulsenheimer A, Lucas M, Seth NP, Tilman Gerlach J, Gruener NH, Loughry A, Pape GR, Wucherpfennig KW, Diepolder HM, Klenerman P. Transient immunological control during acute hepatitis C virus infection: ex vivo analysis of helper T-cell responses. J Viral Hepat 2006; 13:708-14. [PMID: 16970603 PMCID: PMC4515975 DOI: 10.1111/j.1365-2893.2006.00747.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) readily sets up persistence after acute infection. Cellular immune responses are thought to play a major role in control of the virus. Failure of CD4+ T-cell responses in acute disease is associated with viral persistence but the dynamics of this are poorly understood. We aimed to assess such responses using a novel set of Class II tetrameric complexes (tetramers) to study helper T-cells ex vivo in acute disease. We analysed the HCV-specific CD4+ T-cell response in a patient with acute hepatitis c infection. We were able to track the virus-specific CD4+ T-cells directly ex vivo with HLA DR4 tetramers. Proliferative responses were absent initially, recovered as viral load dropped and were lost again during relapse. Longitudinal tetramer analyses showed expanded populations of antiviral CD4+ T-cells throughout acute infection despite lack of proliferation. A pattern of transient CD4+ T-cell proliferative responses as HCV is partially controlled is observed. Failure to control virus is associated with emergence of 'dysfunctional' CD4+ T-cell populations. Failure to control HCV in acute disease may relate to the capacity to sustain efficient immune responses as virus attempts to 'bounce back' after partial control.
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Affiliation(s)
- A Ulsenheimer
- Institute for Immunology, University of Munich, Munich, Germany.
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32
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Abstract
Hepatitis B virus (HBV) is a major cause of chronic liver inflammation worldwide. Recent knowledge of the virological and immunological events secondary to HBV infection has increased our understanding of the mechanisms involved in viral clearance and persistence. In this review, how the early virological and immunological events might influence the development of a coordinate activation of adaptive immunity necessary to control HBV infection is analysed. The mechanism(s) by which high levels of viral antigens, liver immunological features, regulatory cells and dendritic cell defects might maintain the HBV-specific immunological collapse, typical of chronic hepatitis B patients, is also examined.
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Affiliation(s)
- Antonio Bertoletti
- The UCL Institute of Hepatology, University College of London, 69-75 Chenies Mews, London WC1E 6HX, UK
| | - Adam J Gehring
- The UCL Institute of Hepatology, University College of London, 69-75 Chenies Mews, London WC1E 6HX, UK
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33
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Brooks DG, McGavern DB, Oldstone MBA. Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection. J Clin Invest 2006; 116:1675-85. [PMID: 16710479 PMCID: PMC1462941 DOI: 10.1172/jci26856] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2005] [Accepted: 04/04/2006] [Indexed: 12/12/2022] Open
Abstract
Failure to clear persistent viral infections results from the early loss of T cell activity. A pertinent question is whether the immune response is programmed to fail or if nonresponsive T cells can specifically be fixed to eliminate infection. Although evidence indicates that T cell expansion is permanently programmed during the initial priming events, the mechanisms that determine the acquisition of T cell function are less clear. Herein we show that in contrast to expansion, the functional programming of T cell effector and memory responses in vivo in mice is not hardwired during priming but is alterable and responsive to continuous instruction from the antigenic environment. As a direct consequence, dysfunctional T cells can be functionally reactivated during persistent infection even after an initial program of inactivation has been instituted. We also show that early therapeutic reductions in viral replication facilitate the preservation of antiviral CD4+ T cell activity, enabling the long-term control of viral replication. Thus, dysfunctional antiviral T cells can regain activity, providing a basis for future therapeutic strategies to treat persistent viral infections.
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Affiliation(s)
- David G Brooks
- Viral Immunobiology Laboratory, Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, California, USA.
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34
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Koeppe JR, Campbell TB, Rapaport EL, Wilson CC. HIV-1-Specific CD4+ T-Cell Responses Are Not Associated With Significant Viral Epitope Variation in Persons With Persistent Plasma Viremia. J Acquir Immune Defic Syndr 2006; 41:140-8. [PMID: 16394844 DOI: 10.1097/01.qai.0000195608.32885.38] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To determine whether increased sequence variation occurs in regions of endogenous HIV-1 targeted by HIV-1-specific CD4 T cells. The presence of increased variation would be suggestive of immune evasion by HIV-1. DESIGN We performed a cross-sectional study of untreated HIV-1-infected subjects measuring HIV-1-specific interferon (IFN)-gamma-secreting CD4 T-cell responses against epitopes in Gag p17 and p24 and concurrent endogenous plasma HIV-1 RNA epitope sequence variation. METHODS CD8- depleted IFNgamma enzyme-linked immunospot assays were used to identify regions of HIV-1 Gag recognized by CD4 T cells. Reverse transcriptase polymerase chain reaction and TA cloning were used to sequence endogenous plasma HIV-1 virus and identify variants. RESULTS CD4 T-cell epitopes in Gag p17 and p24 were identified in 5 individuals, and concurrent sequence information on endogenous HIV-1 was obtained in 4 of these individuals. Endogenous plasma HIV-1 RNA sequencing revealed no intrapatient amino acid sequence variation through identified epitopes. CONCLUSIONS In these chronically infected viremic subjects, circulating IFNgamma-secreting CD4 T-cell responses were directed against epitope sequences found in the predominant strain of endogenous circulating plasma HIV-1, suggesting that escape from CD4 T-cell responses is not a common process in vivo.
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Affiliation(s)
- John R Koeppe
- Division of Infectious Diseases and Clinical Immunology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
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35
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Benigni F, Zimmermann VS, Hugues S, Caserta S, Basso V, Rivino L, Ingulli E, Malherbe L, Glaichenhaus N, Mondino A. Phenotype and homing of CD4 tumor-specific T cells is modulated by tumor bulk. THE JOURNAL OF IMMUNOLOGY 2005; 175:739-48. [PMID: 16002669 DOI: 10.4049/jimmunol.175.2.739] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Technical difficulties in tracking endogenous CD4 T lymphocytes have limited the characterization of tumor-specific CD4 T cell responses. Using fluorescent MHC class II/peptide multimers, we defined the fate of endogenous Leishmania receptor for activated C kinase (LACK)-specific CD4 T cells in mice bearing LACK-expressing TS/A tumors. LACK-specific CD44(high)CD62L(low) CD4 T cells accumulated in the draining lymph nodes and had characteristics of effector cells, secreting IL-2 and IFN-gamma upon Ag restimulation. Increased frequencies of CD44(high)CD62L(low) LACK-experienced cells were also detected in the spleen, lung, liver, and tumor itself, but not in nondraining lymph nodes, where the cells maintained a naive phenotype. The absence of systemic redistribution of LACK-specific memory T cells correlated with the presence of tumor. Indeed, LACK-specific CD4 T cells with central memory features (IL-2(+)IFN-gamma(-)CD44(high)CD62L(high) cells) accumulated in all peripheral lymph nodes of mice immunized with LACK-pulsed dendritic cells and after tumor resection. Together, our data demonstrate that although tumor-specific CD4 effector T cells producing IFN-gamma are continuously generated in the presence of tumor, central memory CD4 T cells accumulate only after tumor resection. Thus, the continuous stimulation of tumor-specific CD4 T cells in tumor-bearing mice appears to hinder the systemic accumulation of central memory CD4 T lymphocytes.
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Affiliation(s)
- Fabio Benigni
- Cancer Immunotherapy and Gene Therapy Program, S. Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy
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Abstract
Persistent virus infections create specific problems for their hosts. Although the dynamics of immune responses after acute infection are well studied and very consistent, especially in mouse models, the patterns of responses noted during persistent infection are more complex and differ depending on the infection. In particular, CD8(+) T cell responses differ widely in quantity and quality. In this review we examine these diverse responses and ask how they may arise; in particular, we discuss the function of antigen re-encounter and the CD4(+) T cell responses to and the escape strategies of specific viruses. We focus on studies of four main human pathogens, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus and hepatitis C virus, and their animal models.
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Affiliation(s)
- Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
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37
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Brooks DG, Teyton L, Oldstone MBA, McGavern DB. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J Virol 2005; 79:10514-27. [PMID: 16051844 PMCID: PMC1182641 DOI: 10.1128/jvi.79.16.10514-10527.2005] [Citation(s) in RCA: 191] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Effective T-cell responses are critical to eradicate acute viral infections and prevent viral persistence. Emerging evidence indicates that robust, early CD4 T-cell responses are important in effectively sustaining CD8 T-cell activity. Herein, we illustrate that virus-specific CD4 T cells are functionally inactivated early during the transition into viral persistence and fail to produce effector cytokines (i.e., interleukin-2 and tumor necrosis factor alpha), thereby compromising an efficient and effective antiviral immune response. Mechanistically, the inactivation occurs at the cellular level and is not an active process maintained by regulatory T cells or antigen-presenting cells. Importantly, a small subpopulation of cells is able to resist inactivation and persist into the chronic phase of infection. However, the virus-specific CD4 T-cell population ultimately undergoes a second round of inactivation, and the cells that had retained functional capacity fail to respond to rechallenge in an acute time frame. Based on these results we propose a biological mechanism whereby early CD4 T-cell inactivation leads to a subsequent inability to sustain cytotoxic T-lymphocyte function, which in turn facilitates viral persistence. Moreover, these studies are likely relevant to chronic/persistent infections of humans (e.g., human immunodeficiency virus, hepatitis C virus, and hepatitis B virus) by providing evidence that a reservoir of virus-specific CD4 T cells can remain functional during chronic infection and represent a potential therapeutic target to stimulate the immune response and establish control of infection.
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Affiliation(s)
- David G Brooks
- Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
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38
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Orozco JJ, Carter JJ, Koutsky LA, Galloway DA. Humoral immune response recognizes a complex set of epitopes on human papillomavirus type 6 l1 capsomers. J Virol 2005; 79:9503-14. [PMID: 16014913 PMCID: PMC1181614 DOI: 10.1128/jvi.79.15.9503-9514.2005] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Although epitope mapping has identified residues on the human papillomavirus (HPV) major capsid protein (L1) that are important for binding mouse monoclonal antibodies, epitopes recognized by human antibodies are not known. To map epitopes on HPV type 6 (HPV6) L1, surface-exposed loops were mutated to the corresponding sequence of HPV11 L1. HPV6 L1 capsomers had one to six regions mutated, including the BC, DE, EF, FG, and HI loops and the 139 C-terminal residues. After verifying proper conformation, hybrid capsomers were used in enzyme-linked immunosorbent assays with 36 HPV6-seropositive sera from women enrolled in a study of incident HPV infection. Twelve sera were HPV6 specific, while the remainder reacted with both HPV6 and HPV11 L1. By preadsorption studies, 6/11 of these sera were shown to be cross-reactive. Among the HPV6-specific sera there was no immunodominant epitope recognized by all sera. Six of the 12 sera recognized epitopes that contained residues from combinations of the BC, DE, and FG loops, one serum recognized an epitope that consisted partially of the C-terminal arm, and three sera recognized complex epitopes to which reactivity was eliminated by switching all five loops. Reactivity in two sera was not eliminated even with all six regions swapped. The patterns of epitope recognition did not change over time in women whose sera were examined 9 years after their first-seropositive visit.
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Affiliation(s)
- Johnnie J Orozco
- Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
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39
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Mwangi W, Brown WC, Splitter GA, Zhuang Y, Kegerreis K, Palmer GH. Enhancement of antigen acquisition by dendritic cells and MHC class II-restricted epitope presentation to CD4+ T cells using VP22 DNA vaccine vectors that promote intercellular spreading following initial transfection. J Leukoc Biol 2005; 78:401-11. [PMID: 15857936 DOI: 10.1189/jlb.1204722] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Induction of immune responses against microbial antigens using DNA is an attractive strategy to mimic the immunity induced by live vaccines. Although DNA vaccines are efficacious in murine models, the requirement for multiple immunizations using high doses in outbred animals and humans has hindered deployment. This requirement is, in part, a result of poor vaccine spreading and suboptimal DC transfection efficiency. Incorporation of a signal that directs intercellular spreading of a DNA-encoded antigen is proposed to mimic live vaccine spreading and increase dendritic cell (DC) presentation. Bovine herpes virus 1 tegument protein, BVP22, is capable of trafficking to surrounding cells. To test the hypothesis that BVP22 enhances spreading and antigen presentation to CD4+ T cells, a DNA construct containing BVP22, fused in-frame to a sequence encoding a T cell epitope of Anaplasma marginale, was generated. A construct with reversed BVP22 sequence served as a negative control. Immunocytometric analysis of transfected primary keratinocytes, human embryonic kidney 293, COS-7, and Chinese hamster ovary cells showed that BVP22 enhanced intercellular spreading by > or = 150-fold. Flow cytometric analysis of antigen-presenting cells (APCs) positively selected from cocultures of transfected cells and APCs showed that 5% of test APCs were antigen-positive, compared with 0.6% of control APCs. Antigen-specific CD4+ T cell proliferation demonstrated that BVP22 enhanced DC antigen presentation by > or = 20-fold. This first report of the ability of BVP22 to increase DNA-encoded antigen acquisition by DCs and macrophages, with subsequent enhancement of major histocompatibility complex class II-restricted CD4+ T cell responses, supports incorporating a spreading motif in a DNA vaccine to target CD4+ T cell-dependent immunity in outbred animals.
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Affiliation(s)
- Waithaka Mwangi
- Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA.
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40
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Chang JJ, Wightman F, Bartholomeusz A, Ayres A, Kent SJ, Sasadeusz J, Lewin SR. Reduced hepatitis B virus (HBV)-specific CD4+ T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy. J Virol 2005; 79:3038-51. [PMID: 15709024 PMCID: PMC548440 DOI: 10.1128/jvi.79.5.3038-3051.2005] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronically infected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4(+) and CD8(+) T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers (n = 34) were studied, including individuals never treated for HBV infection (n = 7), HBV-infected individuals receiving anti-HBV therapy (n = 13), and HIV-1-HBV-coinfected individuals receiving anti-HBV therapy (n = 14). CD4(+) and CD8(+) HBV-specific T-cell responses were more frequently detected and the CD8(+) T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBV-specific T-cell response and HBV viral load. HBV-specific CD4(+) and CD8(+) T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8(+) T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4(+) T-cell responses were significantly reduced in HIV-1-HBV-coinfected individuals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.
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Affiliation(s)
- J Judy Chang
- Infectious Diseases Unit, Alfred Hospital, Commercial Rd., Melbourne, Victoria 3004, Australia
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41
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Price DA, West SM, Betts MR, Ruff LE, Brenchley JM, Ambrozak DR, Edghill-Smith Y, Kuroda MJ, Bogdan D, Kunstman K, Letvin NL, Franchini G, Wolinsky SM, Koup RA, Douek DC. T cell receptor recognition motifs govern immune escape patterns in acute SIV infection. Immunity 2005; 21:793-803. [PMID: 15589168 DOI: 10.1016/j.immuni.2004.10.010] [Citation(s) in RCA: 245] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2004] [Revised: 09/29/2004] [Accepted: 10/13/2004] [Indexed: 11/18/2022]
Abstract
Escape from adaptive T cell immunity through transmutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T cell receptor (TCR)-antigen interface are unknown. Here, we show that mutational escape is intimately linked to the structural configuration of constituent TCR clonotypes within virus-specific CD8(+) T cell populations. Analysis of 3416 SIV-specific TCR sequences revealed that polyclonal T cell populations characterized by highly conserved TCRB CDR3 motifs were rendered ineffectual by single residue mutations in the cognate viral epitope. Conversely, diverse clonotypic repertoires without discernible motifs were not associated with viral escape. Thus, fundamental differences in the mode of antigen engagement direct the pattern of adaptive viral evolution. These findings have profound implications for the development of vaccines that elicit T cell immunity to combat pathogens with unstable genomes.
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Affiliation(s)
- David A Price
- Human Immunology Section, Vaccine Research Center, NIAID/NIH, Bethesda, MD 20892, USA
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42
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Whitton JL, Slifka MK, Liu F, Nussbaum AK, Whitmire JK. The regulation and maturation of antiviral immune responses. Adv Virus Res 2005; 63:181-238. [PMID: 15530562 PMCID: PMC7125551 DOI: 10.1016/s0065-3527(04)63003-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- J Lindsay Whitton
- Department of Neuropharmacology, CVN-9, The Scripps Research Institute, La Jolla, CA 92037, USA
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43
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Missale G, Cariani E, Ferrari C. Role of viral and host factors in HCV persistence: which lesson for therapeutic and preventive strategies? Dig Liver Dis 2004; 36:703-11. [PMID: 15570998 DOI: 10.1016/j.dld.2004.07.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Several lines of evidence support the view that hepatitis C virus is not directly cytopathic for infected host cells and that the immune response plays a central role in the pathogenesis of liver damage. Innate and adaptive immune responses are induced in most individuals infected with hepatitis C virus but are insufficient to eliminate the virus. The mechanisms responsible for this failure are largely unknown but the kinetics of hepatitis C virus replication relative to the priming of the adaptive responses may exert a profound influence on the balance between virus and host. Immediately after hepatitis C virus infection, the virus replicates efficiently, inducing the production of type I interferons. However, the rapid increase in viral replication seems to be ignored by the adaptive immune response, and after a short interval from exposure, viral load can reach levels comparable to those of patients with established persistent infection. The CD8-mediated response shows functional defects, with impaired production of interferon-gamma, low perforin content, decreased capacity of expansion and lysis of target cells. Late appearance and functional defects of T cells in hepatitis C virus infection might be the result of the rapid increase of the viral load that could create the conditions for exhaustion of the adaptive response or reflect an insufficient function of the innate immune response. This possibility is suggested by in vitro studies showing that hepatitis C virus gene products can interfere with the anti-viral activity of type I interferons and natural killer cells as well as with the maturation of dendritic cells. While T-cell defects are reversed in a minority of infected individuals who succeed in controlling the infection, the T-cell impairment becomes progressively more profound as infection progresses to chronicity. In this situation, therapeutic restoration of adaptive responses may represent a rational strategy to obtain resolution of infection and to complement available therapies. The peculiar kinetics of hepatitis C virus replication and T-cell induction soon after infection may have important implications also for the design of protective vaccines since memory responses may not be able to precede the early peak of viral replication. Therefore, vaccines against hepatitis C virus may be unable to prevent infection but may rather be effective in facilitating a self-limited evolution of infection.
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Affiliation(s)
- G Missale
- Division of Infectious Diseases and Hepatology, University of Parma, via Gramsci 14, 43100 Parma, Italy
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44
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Recher M, Hunziker L, Ciurea A, Harris N, Lang KS. Public, private and non-specific antibodies induced by non-cytopathic viral infections. Curr Opin Microbiol 2004; 7:426-33. [PMID: 15358263 DOI: 10.1016/j.mib.2004.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Lymphocytic choriomeningitis virus (LCMV) represents a useful experimental model of murine infection with a non-cytopathic virus, bearing resemblance to HIV and hepatitis C virus (HCV) infections in humans. Recent data from the LCMV model indicate that the humoral immune response that is induced by non-cytopathic viruses is far more complex than previously appreciated. LCMV-induced IgG production is largely polyclonal, with more than 90% of the antibody repertoire constituting non-relevant specificities. A delayed virus-neutralizing antibody response is induced, including specificities directed not only against the parental LCMV-strain present in the host but also cross-specifically against LCMV-variants isolated from other hosts. These findings provide novel insights to aid our understanding of clinically relevant observations that are recorded following human infection with HIV, HCV and dengue viruses.
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Affiliation(s)
- Mike Recher
- Institute for Experimental Immunology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
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45
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Chaui-Berlinck JG, Barbuto JAM, Monteiro LHA. Conditions for pathogen elimination by immune systems. Theory Biosci 2004; 123:195-208. [PMID: 18236099 DOI: 10.1016/j.thbio.2004.01.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
A continuous harvest effort can lead a population to extinction. How an "unconscious" immune system would perpetrate such an effort in order to eliminate a self-replicating antigen (a pathogen) becomes an intriguing problem if the system responses are functions of the pathogen population: the responses cannot be a continuous effort as the pathogen vanishes. On theoretical grounds, we show some qualities an immune response must have to support pathogen elimination. Then, three specific mechanisms are addressed: a pathogen-independent positive feedback loop among the responding cells of the system (e.g., B-lymphocyte and T-helper); the persistence of antigen bound to presenting cells; and the programmed expansion/contraction of a pool of responding cells. The maintenance of responding cells due to these mechanisms is the essential feature to the effective clearance of self-replicating agents. Thus, evolutionarily, the primary function of a helper lymphocyte would be to amplify a response and the primary function of memory would be the very elimination of pathogens.
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Affiliation(s)
- José Guilherme Chaui-Berlinck
- Departamento de Fisiologia, Instituto de Biociências, da Universidade de São Paulo, Rua do Matao tr. 14, 321, 05508-900, São Paulo, SP, Brazil,
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46
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Chien PC, Cohen S, Tuen M, Arthos J, Chen PD, Patel S, Hioe CE. Human immunodeficiency virus type 1 evades T-helper responses by exploiting antibodies that suppress antigen processing. J Virol 2004; 78:7645-52. [PMID: 15220439 PMCID: PMC434093 DOI: 10.1128/jvi.78.14.7645-7652.2004] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
T-helper responses are important for controlling chronic viral infections, yet T-helper responses specific to human immunodeficiency virus type 1 (HIV-1), particularly to envelope glycoproteins, are lacking in the vast majority of HIV-infected individuals. It was previously shown that the presence of antibodies to the CD4-binding domain (CD4bd) of HIV-1 glycoprotein 120 (gp120) prevents T-helper responses to gp120, but their suppressive mechanisms were undefined (C. E. Hioe et al., J. Virol. 75:10950-10957, 2001). The present study demonstrates that gp120, when complexed to anti-CD4bd antibodies, becomes more resistant to proteolysis by lysosomal enzymes from antigen-presenting cells such that peptide epitopes are not released and presented efficiently by major histocompatibility complex class II molecules to gp120-specific CD4 T cells. Antibodies to other gp120 regions do not confer this effect. Thus, HIV may evade anti-viral T-helper responses by inducing and exploiting antibodies that conceal the virus envelope antigens from T cells.
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Affiliation(s)
- Peter C Chien
- Department of Pathology, New York University School of Medicine and Veterans Affairs, New York Harbor Healthcare System, New York, NY 10010, USA
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47
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Shoukry NH, Sidney J, Sette A, Walker CM. Conserved hierarchy of helper T cell responses in a chimpanzee during primary and secondary hepatitis C virus infections. THE JOURNAL OF IMMUNOLOGY 2004; 172:483-92. [PMID: 14688358 DOI: 10.4049/jimmunol.172.1.483] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Control of hepatitis C virus (HCV) infection could be influenced by the timing and magnitude of CD4+ T cell responses against individual epitopes. We characterized CD4+ T cells targeting seven Pan troglodytes (Patr) class II-restricted epitopes during primary and secondary HCV infections of a chimpanzee. All Patr-DR-restricted HCV epitopes bound multiple human HLA-DR molecules, indicating the potential for overlap in epitopes targeted by both species. Some human MHC class II molecules efficiently stimulated IL-2 production by chimpanzee virus-specific T cell clones. Moreover, one conserved epitope designated NS3(1248) (GYKVLVLNPSV) overlapped a helper epitope that is presented by multiple HLA-DR molecules in humans who spontaneously resolved HCV infection. Resolution of primary infection in the chimpanzee was associated with an initial wave of CD4+ T cells targeting a limited set of dominant epitopes including NS3(1248.) A second wave of low-frequency CD4+ T cells targeting other subdominant epitopes appeared in blood several weeks later after virus replication was mostly contained. During a second infection 7 years later, CD4+ T cells against all epitopes appeared in blood sooner and at higher frequencies but the pattern of dominance was conserved. In summary, primary HCV infection in this individual was characterized by T cell populations targeting two groups of MHC class II-restricted epitopes that differed in frequency and kinetics of appearance in blood. The hierarchial nature of the CD4+ T cell response, if broadly applicable to other HCV-infected chimpanzees and humans, could be a factor governing the outcome of HCV infection.
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Affiliation(s)
- Naglaa H Shoukry
- Center for Vaccines and Immunity, Columbus Children's Research Institute, 700 Children's Drive, Columbus, OH 43205, USA
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48
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Day CL, Walker BD. Progress in defining CD4 helper cell responses in chronic viral infections. ACTA ACUST UNITED AC 2004; 198:1773-7. [PMID: 14676292 PMCID: PMC2194149 DOI: 10.1084/jem.20031947] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Cheryl L Day
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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49
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Cohen S, Tuen M, Hioe CE. Propagation of CD4+ T cells specific for HIV type 1 envelope gp120 from chronically HIV type 1-infected subjects. AIDS Res Hum Retroviruses 2003; 19:793-806. [PMID: 14585210 DOI: 10.1089/088922203769232593] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
HIV-specific CD4+ T cell responses, in particular to the HIV envelope antigen gp120, are often undetectable in the peripheral blood of HIV-infected individuals. The failure to detect these cells poses a significant impediment to studying the T cell populations that are considered to be essential for controlling HIV infection and has led to speculation that these cells are entirely depleted during HIV infection. This study was designed to test whether gp120-specific CD4+ T cells exist in HIV-infected subjects and can be expanded from peripheral blood mononuclear cells by in vitro stimulation with the gp120 antigen, allowing better characterization of these cells. Although gp120-specific T cell responses were barely observed in patient cells ex vivo before antigenic stimulation, CD4+ T cells specific for gp120 were successfully propagated from the blood of each asymptomatic chronically HIV-infected subject studied. The dominant epitopes recognized by gp120-specific CD4+ T cells from these HIV-infected subjects were mapped to well-conserved sites in the C1 and C2 domains of gp120. Two CD4+ T cell lines recognizing these two regions were subsequently established. The CD4+ T cell lines proliferated and produced interferon gamma in response to the specific epitopes, and the responses were MHC class II restricted. These T cell lines also exhibited cross-reactivity with gp120 from T cell line-adapted HIV-1 strains IIIB and MN, as well as with gp120 from primary isolates SF33 (subtype B), CA1 (subtype A), and CA10 (subtype A/E). The data demonstrate that CD4+ T cells specific for gp120 are not entirely depleted from the peripheral blood of chronically HIV-infected subjects; these cells are present in low numbers but can be expanded after antigenic stimulation in vitro.
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Affiliation(s)
- Sandra Cohen
- Veteran Affairs New York Harbor Healthcare System and Department of Pathology, New York University School of Medicine, New York, New York 10010, USA
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50
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Abstract
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.
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Affiliation(s)
- Antonio Bertoletti
- Institute of Hepatology, University College London, Royal Free and University College of London Medical School, London, UK.
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