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Yuan H, Jiao Y, Gao J, Wang T, Xia Y, Li K, Yang Y, Zhang J, Bao H, Wang L, Sun P, Li D, Li P, Cao Y, Zhao Z, Liu Z, Lu Z, Liu Y, Bai X. Enhancement of immune responses to classical swine fever virus E2 in mice by fusion or mixture with the porcine IL-28B. Appl Microbiol Biotechnol 2025; 109:44. [PMID: 39945936 PMCID: PMC11825588 DOI: 10.1007/s00253-024-13399-6] [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: 09/13/2024] [Revised: 12/23/2024] [Accepted: 12/28/2024] [Indexed: 02/16/2025]
Abstract
The E2 subunit vaccine has been considered a promising alternative to an attenuated classical swine fever (CSF) vaccine. However, it fails to induce a good cellular immune response. Given that immunogenic adjuvants can regulate the cellular immunity to achieve a maximum efficacy against antigens, immunostimulatory effects of porcine IL-28B on the CSF virus (CSFV) E2 subunit vaccine were evaluated in the present study. We expressed recombinant proteins E2-IL28B, E2, and IL-28B using CHO-S mammalian cells as an antigen expression platform, and three types of CSFV E2 subunit vaccines based on antigens E2-IL28B, E2 + IL-28B, and E2 were prepared, respectively. We found that both E2-IL28B and E2 + IL-28B antigens exhibited superior immunogenicity with dramatically induced antibody titers and neutralizing antibody levels than the E2 alone. Moreover, E2-IL28B or E2 + IL-28B, instead of E2, boosted cellular immune responses via obviously increasing the percentages of CD3+CD4+ T lymphocytes, promoting the lymphocyte proliferations, and enhancing the release of Th1-type cytokines. All results revealed that the inclusion of IL-28B, whether fused or mixed with E2, significantly elevated E2-induced immune potencies, suggesting that IL-28B could be used as a molecular adjuvant to optimize the design of E2 subunit vaccine for more effective controls of the CSF disease. KEY POINTS: • New CSF E2 subunit vaccine candidates were developed in which IL-28B was an immunoadjuvant • IL-28B significantly elevated the E2-induced immune potency whether it was fused or mixed with E2 • This study provided novel insights into the immunoregulatory properties of IL-28B used for the optimized subunit vaccine design.
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Affiliation(s)
- Hong Yuan
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Yunjuan Jiao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Jie Gao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Tao Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Yingju Xia
- National Reference Laboratory for Classical Swine Fever, China Institute of Veterinary Drug Control, Beijing, 100081, China
| | - Kun Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China
| | - Yuxuan Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Jing Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Huifang Bao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Lihao Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Pu Sun
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Dong Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Pinghua Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Yimei Cao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China
| | - Zhixun Zhao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Zaixin Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China
| | - Zengjun Lu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China.
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China.
| | - Yebing Liu
- National Reference Laboratory for Classical Swine Fever, China Institute of Veterinary Drug Control, Beijing, 100081, China.
| | - Xingwen Bai
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China.
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China.
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Zhou Y, Zhang T, Wang Z, Xu X. Augmented immunogenicity of the HPV16 DNA vaccine via dual adjuvant approach: integration of CpG ODN into plasmid backbone and co-administration with IL-28B gene adjuvant. Virol J 2025; 22:3. [PMID: 39780219 PMCID: PMC11707914 DOI: 10.1186/s12985-024-02604-7] [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: 04/28/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Therapeutic human papillomavirus (HPV) DNA vaccine is an attractive option to control existed HPV infection and related lesions. The two early viral oncoproteins, E6 and E7, are continuously expressed in most HPV-related pre- and cancerous cells, and are ideal targets for therapeutic vaccines. We have previously developed an HPV 16 DNA vaccine encoding a modified E7/HSP70 (mE7/HSP70) fusion protein, which demonstrated significant antitumor effects in murine models. In this study, we employed multifaceted approach to enhance the potency of the HPV16 DNA vaccine. Strategies including inserting CpG oligodeoxynucleotide (CpG ODNs) into the vaccine vector backbone, selecting cytokine gene adjuvants, combining plasmids encoding mE6/HSP70 and mE7/HSP70, and utilizing electroporation for vaccination. Our findings revealed that mice immunized with CpG-modified vaccines, coupled with an IL-28B gene adjuvant exhibited heightened antigen-specific CD8+ T cell responses. Additionally, the combination of mE6/HSP70 and mE7/HSP70 plasmids synergistically enhanced the specific CD8+ T cell response. Furthermore, vaccination with CpG-modified mE7/HSP70 and mE6/HSP70 plasmids, alongside the Interleukin-28B (IL-28B) gene adjuvant, generated substantial preventive and therapeutic antitumor effects against HPV E6- and E7-expressing tumors in C57BL/6 mice. These results suggested that integrating these multiple strategies into an HPV DNA vaccine holds promise for effectively controlling HPV infection and related diseases.
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Affiliation(s)
- Yan Zhou
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Department of Immunology, Hebei North University, Zhangjiakou, China
| | - Ting Zhang
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Zhirong Wang
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Xuemei Xu
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
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Amoia CF, Chengula AA, Hakizimana JN, Wambura PN, Munir M, Misinzo G, Weger-Lucarelli J. Development of a genotype-matched Newcastle disease DNA vaccine candidate adjuvanted with IL-28b for the control of targeted velogenic strains of Newcastle disease virus in Africa. Vet Res Commun 2024; 49:33. [PMID: 39585481 PMCID: PMC11588948 DOI: 10.1007/s11259-024-10590-y] [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: 07/11/2024] [Accepted: 10/10/2024] [Indexed: 11/26/2024]
Abstract
Newcastle disease virus (NDV) is an extremely contagious and deadly virus that affects numerous bird species, posing serious threats to poultry production on a global scale. In addition to implementing biosecurity practices in farming systems, vaccination remains the most effective means of controlling Newcastle disease (ND). However, while existing commercial vaccines provide some level of protection, the effectiveness of these vaccines can be questionable, particularly in field settings where the complexity of vaccination program implementation poses significant challenges, especially against virulent genotypes of NDV. A genotype-matched NDV DNA vaccine could potentially offer a more effective vaccination approach than currently available live attenuated vaccines. By being specifically tailored to match circulating strains, such a vaccine might improve efficacy and reduce the risk of vaccine failure due to genotype mismatch. To develop an alternative vaccine approach, two ND DNA vaccines were constructed in this study. Each vaccine developed in this study contains the fusion (F) and haemagglutinin-neuraminidase (HN) genes of a virulent NDV genotype VII isolate from Tanzania. Interferon lambda-3 (IFNλ3; IL-28b), which has demonstrated capacity to significantly enhance specific adaptive immune responses and decreased levels of inflammatory cytokines, as well as improved protective responses at a high viral challenge dose, was included in one of the developed vaccines. These plasmids were designated pTwist-F-HN-VII-IL28b and pTwist-F-HN-VII. The two plasmids differed in that pTwist-F-HN-VII-IL28b contained the cytokine adjuvant IL-28b. Transfection of cells and subsequent immunofluorescence assays indicated that both plasmids expressed high levels of NDV F-HN proteins. In vivo immunization demonstrated that chicks intramuscularly immunized with pTwist-F-HN-VII-IL28b exhibited significant immune responses compared to chicks immunized with pTwist-F-HN-VII or the commonly used LaSota vaccine (LaSota), which was used as a control. The protective efficacy of pTwist-F-HN-VII-IL28b was 80% after challenge with the highly virulent NDV strain ON148423, compared to 60% for chicks vaccinated using LaSota, and pTwist-F-HN-VII. The findings of this study indicate that IL-28b can be employed as a molecular adjuvant for NDV vaccines. This study represents a key milestone in Newcastle disease vaccine research, particularly in the development of a genotype-matched DNA vaccine candidate. Additionally, this study demonstrated that the combination of F, HN, and IL-28b elicits an efficacious immune response against virulent NDV strains.
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Affiliation(s)
- Charlie F Amoia
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania.
- SACIDS Foundation for One Health, SACIDS Africa Centre of Excellence for Infectious Diseases, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania.
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, 24061, USA.
| | - Augustino A Chengula
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania
| | - Jean N Hakizimana
- OR Tambo Africa Research Chair for Viral Epidemics, SACIDS Foundation for One Health, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania
| | - Philemon N Wambura
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania
| | - Muhammad Munir
- Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YG, UK
| | - Gerald Misinzo
- Department of Veterinary Microbiology, Parasitology and Biotechnology, Sokoine University of Agriculture, P. O. Box 3019, Morogoro, 67125, Tanzania
- SACIDS Foundation for One Health, SACIDS Africa Centre of Excellence for Infectious Diseases, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania
- OR Tambo Africa Research Chair for Viral Epidemics, SACIDS Foundation for One Health, Sokoine University of Agriculture, P. O. Box 3297, Morogoro, 67125, Tanzania
| | - James Weger-Lucarelli
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, 24061, USA.
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, 24060, USA.
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Liu RJ, Yang GB. Molecular characteristics of rhesus macaque interferon-lambda receptor 1 (mmuIFNLR1): Sequence identity, distribution and alteration after simian-human immunodeficiency virus infection in the skin and buccal mucosa. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2024; 160:105236. [PMID: 39103005 DOI: 10.1016/j.dci.2024.105236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/01/2024] [Accepted: 08/01/2024] [Indexed: 08/07/2024]
Abstract
Interferon-lambda receptor 1 (IFNLR1) is the key to interferon-lambda's biological activities. Rhesus macaques (Macaca mulatta) are supposedly more suitable for translational studies on interferon lambda-associated human diseases, yet little is known about their IFNLR1 (mmuIFNLR1). In this study, we cloned the coding sequence of mmuIFNLR1, examined its variants, and determined the distribution of mmuIFNLR1 mRNA and immunoreactivity in the buccal mucosa and arm skin of normal and immunodeficiency virus (SHIV/SIV) infected rhesus macaques. It was found that mmuIFNLR1 has 93.1% amino acid sequence identity to that of humans; all the amino acid residues of mmuIFNLR1 signal peptide, transmembrane region, PxxLxF motif and those essential for ligand binding are identical to that of humans; 6 variants of mmuIFNLR1, including the ones corresponding to that of humans were detected; IFNLR1 immunoreactivity was localized in primarily the epithelia of buccal mucosa and arm skin; SHIV/SIV infection could affect the levels of mmuIFNLR1 mRNA and immunoreactivity. These data expanded our knowledge on mmuIFNLR1 and provided a scientific basis for rational use of rhesus macaques in studies of IFN-λ associated human diseases like AIDS. Future studies testing IFNLR1-targeting therapeutics in rhesus macaques were warranted.
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Affiliation(s)
- Rui-Jie Liu
- National Center for AIDS/STD Control and Prevention, China-CDC, Beijing, 102206, PR China
| | - Gui-Bo Yang
- National Center for AIDS/STD Control and Prevention, China-CDC, Beijing, 102206, PR China.
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Cao L, Qian W, Li W, Ma Z, Xie S. Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response. Front Immunol 2023; 14:1250541. [PMID: 37809098 PMCID: PMC10556530 DOI: 10.3389/fimmu.2023.1250541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
Previously, it was believed that type III interferon (IFN-III) has functions similar to those of type I interferon (IFN-I). However, recently, emerging findings have increasingly indicated the non-redundant role of IFN-III in innate antiviral immune responses. Still, the regulatory activity of IFN-III in adaptive immune response has not been clearly reported yet due to the low expression of IFN-III receptors on most immune cells. In the present study, we reviewed the adjuvant, antiviral, antitumor, and disease-moderating activities of IFN-III in adaptive immunity; moreover, we further elucidated the mechanisms of IFN-III in mediating the adaptive antiviral immune response in a thymic stromal lymphopoietin (TSLP)-dependent manner, a pleiotropic cytokine involved in mucosal adaptive immunity. Research has shown that IFN-III can enhance the antiviral immunogenic response in mouse species by activating germinal center B (GC B) cell responses after stimulating TSLP production by microfold (M) cells, while in human species, TSLP exerts OX40L for regulating GC B cell immune responses, which may also depend on IFN-III. In conclusion, our review highlights the unique role of the IFN-III/TSLP axis in mediating host adaptive immunity, which is mechanically different from IFN-I. Therefore, the IFN-III/TSLP axis may provide novel insights for clinical immunotherapy.
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Affiliation(s)
- Luhong Cao
- Department of Otolaryngology Head and Neck Surgery Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Weiwei Qian
- Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, and Disaster Medical Center, Sichuan University, Chengdu, Sichuan, China
| | - Wanlin Li
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Shenzhen, China
| | - Zhiyue Ma
- Department of Otolaryngology Head and Neck Surgery Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shenglong Xie
- Department of Thoracic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Zhang X, Wang S, Zhu Y, Zhang M, Zhao Y, Yan Z, Wang Q, Li X. Double-edged effects of interferons on the regulation of cancer-immunity cycle. Oncoimmunology 2021; 10:1929005. [PMID: 34262796 PMCID: PMC8253121 DOI: 10.1080/2162402x.2021.1929005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Interferons (IFNs) are a large family of pleiotropic cytokines that regulate both innate and adaptive immunity and show anti-cancer effects in various cancer types. Moreover, it was revealed that IFN signaling plays critical roles in the success of cancer therapy strategies, thereby enhancing their therapeutic effects. However, IFNs have minimal or even adverse effects on cancer eradication, and mediate cancer immune escape in some instances. Thus, IFNs have a double-edged effect on the cancer immune response. Recent studies suggest that IFNs regulate each step of the cancer immunity-cycle, consisting of cancer antigen release, presentation of antigens and activation of T cells, trafficking and infiltration of effector T cells into the tumor microenvironment, and recognition and killing of cancer cells, which contributes to our understanding of the mechanisms of IFNs in regulating cancer immunity. In this review, we focus on IFNs and cancer immunity and elaborate on the roles of IFNs in regulating the cancer-immunity cycle.
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Affiliation(s)
- Xiao Zhang
- Department of Stomatology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Pathology, Harbin Medical University, Harbin, China
| | - Song Wang
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Yuanyuan Zhu
- Department of Pathology, Harbin Medical University, Harbin, China
| | - Minghui Zhang
- Department of Oncology, Chifeng City Hospital, Chifeng, China
| | - Yan Zhao
- Department of Oncology, Chifeng City Hospital, Chifeng, China
| | - Zhengbin Yan
- Department of Stomatology, the PeopIe's Hospital of Longhua, Shenzhen, China
| | - Qiuxu Wang
- Department of Stomatology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Stomatology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xiaobo Li
- Department of Stomatology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Pathology, Harbin Medical University, Harbin, China
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Grzegorzewska AE. Genetic Polymorphisms within Interferon-λ Region and Interferon-λ3 in the Human Pathophysiology: Their Contribution to Outcome, Treatment, and Prevention of Infections with Hepatotropic Viruses. Curr Med Chem 2019; 26:4832-4851. [DOI: 10.2174/0929867325666180719121142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 03/21/2018] [Accepted: 07/09/2018] [Indexed: 12/16/2022]
Abstract
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Genetic polymorphisms within the interferon λ (IFN-λ) chromosomal region,
mainly rs12979860 of IFN-λ4 gene (IFNL4), are known as associated with spontaneous hepatitis
C virus (HCV) resolution and sustained viral response to therapy with pegylated interferon-
α and ribavirin. Strong linkage disequilibrium of IFNL4 rs12979860 with IFNL4
rs368234815, which is casually associated with HCV spontaneous and therapeutical eradication,
at least partially explains favorable HCV outcomes attributed to major homozygosity in
rs12979860. Effects of IFN-based antiviral treatment are associated with pretreatment expression
of the IFN-λ1 receptor, expression of hepatic IFN-stimulated genes, production of IFN-
λ4, and preactivation of the JAK-STAT signaling. Nowadays direct-acting antivirals (DAAs)
became a potent tool in the treatment of hepatitis C, but IFN-λs are still under investigation as
potential antivirals and might be an option in HCV infection (DAA resistance, recurrent viremia,
adverse effects).
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Patients with altered immunocompetence are especially prone to infections. In uremic subjects,
polymorphisms within the IFN-λ chromosomal region associate with spontaneous HCV
clearance, similarly like in the non-uremic population. Circulating IFN-λ3 shows a positive
correlation with plasma titers of antibodies to surface antigen of hepatitis B virus (anti-HBs),
which are crucial for protection against hepatitis B virus. More efficient anti-HBs production
in the presence of higher IFN-λ3 levels might occur due to IFN-λ3-induced regulation of indoleamine
2,3-dioxygenase (IDO) expression. IFN-stimulated response element is a part of
IDO gene promoter. It is worth further investigation whether IDO gene, circulating IDO, genetic
polymorphisms within the IFN-λ region, and circulating IFN-λ3 act in concordance in
immunological response to hepatotropic viruses.
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Affiliation(s)
- Alicja E. Grzegorzewska
- Chair and Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat Rev Immunol 2019; 19:614-625. [DOI: 10.1038/s41577-019-0182-z] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2019] [Indexed: 02/07/2023]
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Hemann EA, Gale M, Savan R. Interferon Lambda Genetics and Biology in Regulation of Viral Control. Front Immunol 2017; 8:1707. [PMID: 29270173 PMCID: PMC5723907 DOI: 10.3389/fimmu.2017.01707] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 11/20/2017] [Indexed: 12/14/2022] Open
Abstract
Type III interferons, also known as interferon lambdas (IFNλs), are the most recent addition to the IFN family following their discovery in 2003. Initially, IFNλ was demonstrated to induce expression of interferon-stimulated genes and exert antiviral properties in a similar manner to type I IFNs. However, while IFNλ has been described to have largely overlapping expression and function with type I IFNs, it has become increasingly clear that type III IFNs also have distinct functions from type I IFNs. In contrast to type I IFNs, whose receptor is ubiquitously expressed, type III IFNs signal and function largely at barrier epithelial surfaces, such as the respiratory and gastrointestinal tracts, as well as the blood–brain barrier. In further support of unique functions for type III IFNs, single nucleotide polymorphisms in IFNL genes in humans are strongly associated with outcomes to viral infection. These biological linkages have also been more directly supported by studies in mice highlighting roles of IFNλ in promoting antiviral immune responses. In this review, we discuss the current understanding of type III IFNs, and how their functions are similar to, and different from, type I IFN in various immune cell subtypes and viral infections.
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Affiliation(s)
- Emily A Hemann
- Department of Immunology, Center for Innate Immunity and Immune Diseases, University of Washington, Seattle, WA, United States
| | - Michael Gale
- Department of Immunology, Center for Innate Immunity and Immune Diseases, University of Washington, Seattle, WA, United States
| | - Ram Savan
- Department of Immunology, Center for Innate Immunity and Immune Diseases, University of Washington, Seattle, WA, United States
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Circulating Interferon- λ3, Responsiveness to HBV Vaccination, and HBV/HCV Infections in Haemodialysis Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3713025. [PMID: 29226133 PMCID: PMC5684519 DOI: 10.1155/2017/3713025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/16/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023]
Abstract
The IFN-λ3 gene (IFNL3) plays a role in HCV clearance. We investigated circulating IFN-λ3 and IFNL3 SNPs in haemodialysis patients who differed in their response to HBV vaccination and their HBV/HCV infection status. In 201 patients, plasma IFN-λ3 was determined using ELISA. IFNL3 SNPs (rs12979860, rs8099917) were genotyped using HRM analysis. Differences in IFN-λ3 levels were shown between responders and nonresponders to HBV vaccination and between HBsAg-positive patients and those who developed anti-HBs after infection and became HBsAg negative. HBV vaccine responders without HCV resolution revealed lower IFN-λ3 than noninfected responders. HBsAg/HCV RNA-positive subjects showed lower IFN-λ3 than patients positive only for HCV RNA or subjects who resolved both infections. Circulating IFN-λ3 correlated positively with anti-HBs and negatively with positive HCV RNA testing in the adjusted regression analyses. HBV vaccine nonresponders, HBsAg-positive patients, and subjects with replicating HCV composed a group with unfavourable outcomes. Responders to HBV vaccination, subjects who became HBsAg negative, and those who cleared HCV were analysed as having favourable outcomes. The latter showed higher IFN-λ3 but did not differ in distribution of IFNL3 SNPs compared with subjects with unfavourable outcomes. Higher IFN-λ3 concentrations are associated with response to HBV vaccination, self-limited HBV infection, and HCV resolution.
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Zhou Y, Wang Z, Xu Y, Zhang Z, Hua R, Liu W, Jiang C, Chen Y, Yang W, Kong W. Optimized DNA Vaccine Enhanced by Adjuvant IL28B Induces Protective Immune Responses Against Herpes Simplex Virus Type 2 in Mice. Viral Immunol 2017; 30:601-614. [PMID: 28650722 DOI: 10.1089/vim.2017.0033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Antigen-specific immune responses determine the efficacy of herpes simplex virus type 2 (HSV-2) vaccines. To optimize the immunogenicity of the antigen gD2, we developed the gD2ΔUL25 DNA vaccine encoding HSV-2 glycoprotein D and UL25 gene encoding viral capsid vertex proteins in this study. The gD2 and gD2ΔUL25 DNA vaccines were compared with formalin-inactivated HSV-2 (FI-HSV-2), and results showed a greater protective immune response induced by gD2ΔUL25 than by gD2. Therefore, gD2ΔUL25 was chosen to evaluate further using the IL28B adjuvant. Immunization with gD2ΔUL25/IL28B elicited stronger humoral and T cell immune responses than with gD2ΔUL25 alone. Compared with controls, gD2ΔUL25/IL28B decreased HSV-2 viral loads and induced protective effects against genital tract lesions generated by HSV-2. These findings demonstrated that the prophylactic DNA vaccine gD2ΔUL25 with IL28B adjuvant could enhance the humoral and T cell immune responses, and improve the protective immune response against HSV-2 in female mice compared with FI-HSV-2.
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Affiliation(s)
- Yan Zhou
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
- 2 Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University , Changchun, China
| | - Ziyan Wang
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
| | - Yongqing Xu
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
| | - Zeqiang Zhang
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
- 2 Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University , Changchun, China
| | - Rui Hua
- 3 Hepatic Department, The First Hospital of Jilin University , Changchun, China
| | - Wei Liu
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
- 4 Department of Biotechnology, Jilin Medical University , Jilin, China
| | - Chunlai Jiang
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
- 2 Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University , Changchun, China
| | - Yan Chen
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
- 2 Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University , Changchun, China
| | - Wenying Yang
- 5 Gastroenterol Department, Jilin Province People's Hospital , Changchun, China
| | - Wei Kong
- 1 National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University , Changchun, China
- 2 Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University , Changchun, China
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Benito JM, García-Samaniego J, García M, Madejón A, Martín-Carbonero L, Cabello A, Álvarez B, Górgolas M, Rallón N. Both Hepatitis C Virus-Specific T Cell Responses and IL28B rs12979860 Single-Nucleotide Polymorphism Genotype Influence Antihepatitis C Virus Treatment Outcome in Patients with Chronic Hepatitis C. J Interferon Cytokine Res 2017; 37:278-286. [PMID: 28440692 DOI: 10.1089/jir.2016.0078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite new treatments for hepatitis C virus (HCV) infection, IFNα-based regimens still have clinical relevance in special populations of patients and remain the only therapeutic option for many patients. We sought to elucidate the interplay between two relevant factors (IL28B polymorphism and T cell immune responses) involved in the outcome of this therapy in HCV-infected patients. We evaluated 38 patients infected with HCV genotype 1-17 coinfected with HIV-who were undergoing a full course of pegIFNα/RBV therapy. The interdependence and roles of T cell-mediated immune responses and IL28B rs12979860 single-nucleotide polymorphism genotype as predictors of virological response to anti-HCV treatment in patients with chronic hepatitis C were evaluated using nonparametric tests. Factors associated with rapid virological response (RVR) in univariate analysis were presence of CD4 T cell response against NS3 HCV protein, low baseline HCV-RNA, and IL28B CC genotype. Factors associated with sustained virological response (SVR) in univariate analysis were IL28B CC genotype, low baseline HCV-RNA, and presence of CD4 response against NS2. In the multivariate analysis, low baseline HCV-RNA and NS3-specific CD4 response showed a clear trend toward association with RVR (P = 0.09 and P = 0.07, respectively). Regarding SVR, IL28B CC genotype was the strongest predictor (P = 0.02), with presence of NS2-specific CD4 response showing a clear trend (P = 0.09). HCV-specific T cell response influences the outcome of pegIFNα/RBV therapy regardless of IL28B genotype. HCV-specific T cell responses (adaptive immunity) seem to influence viral clearance both in the short and long term during therapy (RVR and SVR), whereas the influence of the IL28B genotype (innate immunity) may be more relevant to the long-lasting therapeutic effect (SVR).
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Affiliation(s)
- José M Benito
- 1 IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid , Madrid, Spain
- 2 Hospital Universitario Rey Juan Carlos , Móstoles, Spain
| | | | - Marcial García
- 1 IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid , Madrid, Spain
- 2 Hospital Universitario Rey Juan Carlos , Móstoles, Spain
| | - Antonio Madejón
- 3 Hepatology Unit, Hospital Universitario La Paz , Madrid, Spain
- 4 CIBERehd , Madrid, Spain
| | | | - Alfonso Cabello
- 5 Infectious Diseases Unit, Hospital Universitario Fundación Jiménez Díaz , Madrid, Spain
| | - Beatriz Álvarez
- 5 Infectious Diseases Unit, Hospital Universitario Fundación Jiménez Díaz , Madrid, Spain
| | - Miguel Górgolas
- 5 Infectious Diseases Unit, Hospital Universitario Fundación Jiménez Díaz , Madrid, Spain
| | - Norma Rallón
- 1 IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid , Madrid, Spain
- 2 Hospital Universitario Rey Juan Carlos , Móstoles, Spain
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13
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Hayes CN, Chayama K. Interferon stimulated genes and innate immune activation following infection with hepatitis B and C viruses. J Med Virol 2016; 89:388-396. [DOI: 10.1002/jmv.24659] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2016] [Indexed: 12/28/2022]
Affiliation(s)
- C. Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
- Liver Research Project Center; Hiroshima University; Hiroshima Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences; Hiroshima University; Hiroshima Japan
- Liver Research Project Center; Hiroshima University; Hiroshima Japan
- Laboratory for Digestive Diseases; Center for Genomic Medicine, RIKEN; Hiroshima Japan
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14
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Grzegorzewska AE, Świderska MK, Mostowska A, Warchoł W, Jagodziński PP. Antibodies to HBV surface antigen in relation to interferon-λ3 in hemodialysis patients. Vaccine 2016; 34:4866-4874. [PMID: 27595449 DOI: 10.1016/j.vaccine.2016.08.073] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 07/29/2016] [Accepted: 08/24/2016] [Indexed: 12/22/2022]
Abstract
AIM To investigate circulating IFN-λ3 and IFNL3 polymorphisms in hemodialysis (HD) patients differing in HBV surface antigen antibody (anti-HBs) production. METHODS The study included 106 HBV-vaccinated HD patients (88 developed anti-HBs) and 36 HBV-infected HD subjects (27 developed anti-HBs). Plasma IFN-λ3 (enzyme-linked immunosorbent assay) and rs12979860 (C>T) and rs8099917 (T>G) in IFNL3 (high-resolution melting curve analysis) were analyzed with regard to the association with anti-HBs production in response to HBV vaccination or infection. The results were adjusted for gender, age, cause of renal disease, dialysis vintage, dialysis modality, IFN-λ3, and 25(OH)D as appropriate. RESULTS HBV vaccine responders had higher circulating IFN-λ3 (ng/L) than non-responders (120, 36-233 vs. 53, 33-109, P<0.000001). Patients who generated anti-HBs after HBV infection also had higher circulating IFN-λ3 levels than those who did not (133, 35-215 vs. 71, 9-229, P=0.043). The IFN-λ3 concentration correlated with the anti-HBs titer in vaccinated (r=0.614, P<0.000001) and infected patients (r=0.589, P=0.0002). Plasma IFN-λ3 was the only significant indicator of responsiveness to HBV vaccination (adjusted P=0.018) and remained the only significant associate for the development of post-infection anti-HBs (adjusted P=0.049). A plasmaIFN-λ3 level of 85.5ng/L was thecut-off value for theprognosis of an anti-HBs titer below vs. equal to or over 10IU/L in the entire group of HD patients (ROC sensitivity 68.7%, specificity 85.2%, and AUC 0.827). Significant associations were not found between IFN-λ3 and IFNL3 rs12979860. Subjects treated with low flux HD that harbored the TT genotype in rs8099917 showed higher IFN-λ3 levels than patients bearing the G allele in rs8099917 (139, 68-233 vs. 103, 9-208, P=0.049). CONCLUSION In HD patients, circulating IFN-λ3 strongly correlates with anti-HBs production after HBV vaccination and infection. IFNL3 rs8099917 polymorphisms seem to be associated with IFN-λ3 plasma levels in HD subjects.
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Affiliation(s)
- Alicja E Grzegorzewska
- Chair and Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań 60-355, Przybyszewskiego 49, Poland.
| | - Monika K Świderska
- Student Nephrology Research Group, Chair and Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań 60-355, Przybyszewskiego 49, Poland.
| | - Adrianna Mostowska
- Chair and Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań 60-781, Święcickiego 6, Poland.
| | - Wojciech Warchoł
- Chair and Department of Biophysics, Poznan University of Medical Sciences, Poznań 60-780, Grunwaldzka 6, Poland.
| | - Paweł P Jagodziński
- Chair and Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań 60-781, Święcickiego 6, Poland.
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Gene therapy using plasmid DNA-encoded anti-HER2 antibody for cancers that overexpress HER2. Cancer Gene Ther 2016; 23:341-347. [PMID: 27632934 PMCID: PMC5095588 DOI: 10.1038/cgt.2016.37] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 07/19/2016] [Indexed: 01/06/2023]
Abstract
Plasmid DNA-encoded antibodies, or DNA-based monoclonal antibodies (dMAbs), are delivered by intramuscular injection and in vivo electroporation (EP) and are effective in virus neutralization, although they have not been evaluated for tumor gene therapy. Here we investigated whether a dMAb was appropriate for tumor gene therapy. We constructed the expression plasmids coding for the heavy or light chain of a parental murine antibody of Herceptin with the antibody genes codon- and RNA-optimized and fused to the Kozak-IgE leader sequence in pVax1. Transfection of the plasmids into human muscle RD cells resulted in functional expression of the antibody, and this exhibited the same in vitro antiproliferative activity as Herceptin. A single intramuscular injection and in vivo EP of the plasmids (100 μg per head) resulted in high and sustained antibody expression in the sera of normal mice and in effective inhibition of tumor growth in nude mice bearing HER2-positive human breast carcinoma BT474 xenografts. The antitumor efficacy of the anti-HER2 dMAb was similar to that of four doses of intravenously injected 10 mg kg−1 Herceptin. The results demonstrate that the dMAb is effective in the treatment of HER2-positive breast cancer, suggesting that this dMAb may be applicable for tumor gene therapy.
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de Sá KSG, Santana BB, de Souza Ferreira TC, Sousa RCM, Caldas CAM, Azevedo VN, Feitosa RNM, Machado LFA, de Oliveira Guimarães Ishak M, Ishak R, Vallinoto ACR. IL28B gene polymorphisms and Th1/Th2 cytokine levels might be associated with HTLV-associated arthropathy. Cytokine 2016; 77:79-87. [PMID: 26546777 DOI: 10.1016/j.cyto.2015.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 10/30/2015] [Accepted: 11/02/2015] [Indexed: 12/18/2022]
Abstract
The present study is the first investigation of the association between single nucleotide polymorphisms (SNPs - rs8099917, rs12979860 and rs8103142) of the IL28B gene and the development of human T-lymphotropic virus (HTLV)-associated arthropathy (HAA). Individuals with HAA exhibited low interleukin (IL) 6 (p<0.05) and high IL-10 (p<0.05) levels compared with asymptomatic patients. TNF-α/CD4(+) T cell count, TNF-α/CD8(+) T cell count and IFN-γ/proviral load positively correlated in asymptomatic patients. The allelic and genotypic frequencies did not differ between patients with HAA and asymptomatic patients. Seven haplotypes were detected in the investigated population, with haplotype CCT (p<0.05) being the most frequent among the HTLV-infected individuals, while haplotype TTG (p<0.05) was detected in the group with HAA only. Compared with asymptomatic patients, individuals with HAA and genotype TT (rs8099917) exhibited larger numbers of CD8(+) T cells (p<0.05) and higher proviral load levels (p<0.05). Those patients with HAA and genotypes CC (rs12979860) and TT (rs8103142) exhibited high TNF-β (p<0.05) and IFN-γ (p<0.05) levels. Those patients with HAA and genotype CT/TT (rs12979860) exhibited high IL-10 levels (p<0.05). These results suggest that haplotypes CCT and TTG might be associated with susceptibility to HTLV infection and progression to HAA, respectively. Genotype TT (rs8099917) might be a risk factor for elevation of the proviral load and CD8(+) T cell count. In addition, genotypes CC (rs12979860) and TT (rs8103142) seem to be associated with increased TNF-β and IFN-γ levels.
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Affiliation(s)
- Keyla Santos Guedes de Sá
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Bárbara Brasil Santana
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Tuane Carolina de Souza Ferreira
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Rita Catarina Medeiros Sousa
- Tropical Medicine Unit (Núcleo de Medicina Tropical), Federal University of Pará (Universidade Federal do Para), Umarizal, 66050-240 Belém, Pará, Brazil
| | - Cezar Augusto Muniz Caldas
- Tropical Medicine Unit (Núcleo de Medicina Tropical), Federal University of Pará (Universidade Federal do Para), Umarizal, 66050-240 Belém, Pará, Brazil
| | - Vânia Nakauth Azevedo
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Rosimar Neris Martins Feitosa
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Luiz Fernando Almeida Machado
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Marluísa de Oliveira Guimarães Ishak
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Ricardo Ishak
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil
| | - Antonio Carlos Rosário Vallinoto
- Laboratory of Virology (Laboratório de Virologia), Institute of Biological Sciences (Instituto de Ciências Biológicas), Federal University of Pará (Universidade Federal do Pará), Guamá, 66075-110 Belém, Pará, Brazil.
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Modulation of SIV and HIV DNA vaccine immunity by Fas-FasL signaling. Viruses 2015; 7:1429-53. [PMID: 25807052 PMCID: PMC4379579 DOI: 10.3390/v7031429] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 03/10/2015] [Accepted: 03/15/2015] [Indexed: 01/14/2023] Open
Abstract
Signaling through the Fas/Apo-1/CD95 death receptor is known to affect virus-specific cell-mediated immune (CMI) responses. We tested whether modulating the Fas-apoptotic pathway can enhance immune responses to DNA vaccination or lymphocytic choriomeningitis virus (LCMV) infection. Mice were electroporated with plasmids expressing a variety of pro- or anti-apoptotic molecules related to Fas signaling and then either LCMV-infected or injected with plasmid DNA expressing SIV or HIV antigens. Whereas Fas or FasL knockout mice had improved CMI, down-regulation of Fas or FasL by shRNA or antibody failed to improve CMI and was accompanied by increases in regulatory T cells (Treg). Two “adjuvant” plasmids were discovered that significantly enhanced plasmid immunizations. The adjuvant effects of Fas-associated death domain (FADD) and of cellular FLICE-inhibitory protein (cFLIP) were consistently accompanied by increased effector memory T lymphocytes and increased T cell proliferation. This adjuvant effect was also observed when comparing murine infections with LCMV-Armstrong and its persisting variant LCMV-Clone 13. LCMV-Armstrong was cleared in 100% of mice nine days after infection, while LCMV-Clone 13 persisted in all mice. However, half of the mice pre-electroporated with FADD or cFLIP plasmids were able to clear LCMV-Clone 13 by day nine, and, in the case of cFLIP, increased viral clearance was accompanied by higher CMI. Our studies imply that molecules in the Fas pathway are likely to affect a number of events in addition to the apoptosis of cells involved in immunity.
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Ghoneum M, Agrawal S. Mgn-3/biobran enhances generation of cytotoxic CD8+ T cells via upregulation of dec-205 expression on dendritic cells. Int J Immunopathol Pharmacol 2015; 27:523-30. [PMID: 25572732 DOI: 10.1177/039463201402700408] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Arabinoxylan rice bran (MGN-3/Biobran) has been shown to be a potent biological response modifier (BRM) that activates different arms of the immune system, including dendritic cells (DCs), which prime CD4+ helper T-cell responses. The present study explores the ability of MGN-3-activated DCs to prime CD8+ T cells and examines the mechanisms underlying its effect. Human monocyte-derived DCs were treated with MGN-3 (20 and 40 μg/ml). Results indicate that treatment with MGN-3 caused DCs to prime higher granzyme B-expressing CD8+ T cells. Tumor lysate-pulsed MGN-3 DC also increased tumor cell killing compared to DC-stimulated CD8+ T cells. This was associated with: i) increased expression of DEC-205 in MGN-3-activated DCs in a dose-dependent manner; and ii) MGN-3 induced significant production of Type III interferon, IL29, but not Type I IFNs α and β. These results suggest that MGN-3 is a potent natural adjuvant that efficiently activates DCs and may therefore be useful for mounting an efficient immune response against infections and cancer.
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Affiliation(s)
- M Ghoneum
- Charles Drew University of Medicine and Science, Los Angeles, CA, U.S.A
| | - S Agrawal
- Division of Basic and Clinical Immunology, University of California, Irvine, CA, U.S.A
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Galani IE, Koltsida O, Andreakos E. Type III interferons (IFNs): Emerging Master Regulators of Immunity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 850:1-15. [PMID: 26324342 DOI: 10.1007/978-3-319-15774-0_1] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lambda interferons (IFN-λs), type III interferons or interleukins 28 and 29 are the latest addition to the class II cytokine family. They share low homology with the interferon (IFN) and IL-10 cytokine families, yet they exhibit common and unique activities, the full spectrum of which still remains incompletely understood. Although initially described for their antiviral functions, it is now appreciated that IFN-λs also mediate diverse antitumor and immune-modulatory effects, and are key determinants of innate immunity at mucosal sites such as the gastrointestinal and respiratory tracks. Here, we are reviewing the biological functions of IFN-λs, the mechanisms controlling their expression, their downstream effects and their role in the maintenance of homeostasis and disease. We are also exploring the potential application of IFN-λs as novel therapeutics.
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Affiliation(s)
- Ioanna E Galani
- Department of Immunology, Center for Translational and Clinical Research, Biomedical Research Foundation, Academy of Athens, 11527, Athens, Greece
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O’Connor KS, George J, Booth D, Ahlenstiel G. Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. World J Gastroenterol 2014; 20:17830-8. [PMID: 25548481 PMCID: PMC4273133 DOI: 10.3748/wjg.v20.i47.17830] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/14/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general.
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Maldonado L, Teague JE, Morrow MP, Jotova I, Wu TC, Wang C, Desmarais C, Boyer JD, Tycko B, Robins HS, Clark RA, Trimble CL. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci Transl Med 2014; 6:221ra13. [PMID: 24477000 DOI: 10.1126/scitranslmed.3007323] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8(+) T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNβ), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation.
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Affiliation(s)
- Leonel Maldonado
- Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Jessica E Teague
- Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Matthew P Morrow
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Iveta Jotova
- Department of Pathology and Cell Biology and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10025, USA
| | - T C Wu
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Chenguang Wang
- Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Cindy Desmarais
- Adaptive Biotechnologies, 1551 Eastlake Avenue, Seattle, WA 98102, USA
| | - Jean D Boyer
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Benjamin Tycko
- Department of Pathology and Cell Biology and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10025, USA
| | - Harlan S Robins
- Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Rachael A Clark
- Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Cornelia L Trimble
- Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.,Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.,Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
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Trinks J, Hulaniuk ML, Redal MA, Flichman D. Clinical utility of pharmacogenomics in the management of hepatitis C. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:339-47. [PMID: 25382982 PMCID: PMC4222698 DOI: 10.2147/pgpm.s52624] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) was identified for the first time more than 20 years ago. Since then, several studies have highlighted the complicated aspects of this viral infection in relation to its worldwide prevalence, its clinical presentation, and its therapeutic response. Recently, two landmark scientific breakthroughs have moved us closer to the successful eradication of chronic HCV infection. First, response rates in treatment-naïve patients and in prior non-responders to pegylated-interferon-α and ribavirin therapy are increasing as a direct consequence of the development of direct-acting antiviral drugs. Secondly, the discovery of single-nucleotide polymorphisms near the interleukin 28B gene significantly related to spontaneous and treatment-induced HCV clearance represents a milestone in the HCV therapeutic landscape. The implementation of this pharmacogenomics finding as a routine test for HCV-infected patients has enhanced our understanding of viral pathogenesis, has encouraged the design of ground-breaking antiviral treatment regimens, and has become useful for pretreatment decision making. Nowadays, interleukin 28B genotyping is considered to be a key diagnostic tool for the management of HCV-infected patients and will maintain its significance for new combination treatment schemes using direct-acting antiviral agents and even in interferon-free regimens. Such pharmacogenomics insights represent a challenge to clinicians, researchers, and health administrators to transform this information into knowledge with the aim of elaborating safer and more effective therapeutic strategies specifically designed for each patient. In conclusion, the individualization of treatment regimens for patients with hepatitis C, that may lead to a universal cure in future years, is becoming a reality due to recent developments in biomarker and genomic medicine. In light of these advances, we review the scientific evidence and clinical implications of recent findings related to host genetic factors in the management of HCV infection.
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Affiliation(s)
- Julieta Trinks
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina ; National Scientific and Technical Research Council, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Laura Hulaniuk
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Ana Redal
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina ; Instituto Universitario del Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Flichman
- National Scientific and Technical Research Council, Universidad de Buenos Aires, Buenos Aires, Argentina ; Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
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23
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Gorzin Z, Gorzin AA, Tabarraei A, Behnampour N, Irani S, Ghaemi A. Immunogenicity evaluation of a DNA vaccine expressing the hepatitis C virus non-structural protein 2 gene in C57BL/6 mice. IRANIAN BIOMEDICAL JOURNAL 2014; 18:1-7. [PMID: 24375156 DOI: 10.6091/ibj.1231.2013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUNDS Most of the hepatitis C virus (HCV) infections elicit poor immune responses and 75% to 85% of cases become chronic; therefore, the development of an effective vaccine against HCV is of paramount importance. In this study, we aimed to evaluate co-administration of HCV non-Structural Protein 2 and IL-12 DNA vaccines in C57BL/6 mice. METHODS A plasmid encoding full-length HCV NS2 protein (non-structural protein 2) was generated and used to vaccinate mice. Negative control (an empty expression vector) was also employed to evaluate the background response. To investigate immune responses against vaccine, C57BL/6 mice received three doses of the vaccine with a two-week interval. Cellular immunity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay for lymphocyte proliferation, lactate dehydrogenase release for cytotoxic T lymphocyte (CTL) activity and cytokine assay. RESULTS The findings demonstrated that immunization of mice with plasmid expressing HCV NS2 induced CTL response, interferon gamma production, and lymphocyte proliferation compared to negative control. The results also demonstrated that co-administration of IL-12 with the HCV NS2 plasmid induced significantly better immune response in C57BL/6 mice. CONCLUSION DNA vaccine encoding HCV NS2 is an effective candidate that can trigger CTL-based immune response against HCV. In addition, the results suggested that combining the DNA vaccine approach with immune stimulatory cytokines may significantly enhance antigen-specific immune responses.
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Affiliation(s)
- Zahra Gorzin
- Dept. of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ali Akbar Gorzin
- Shiraz HIV/AIDS Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alijan Tabarraei
- Dept. of Microbiology, School of Medicine, Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Naser Behnampour
- Dept. of Statistics, Gorgan Para-Medical School, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shiva Irani
- Dept. of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Amir Ghaemi
- Golestan Research Center of Gastroenterology and Hepatology-GRCGH, Dept. of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.,Shefa Neuroscience Research Center, Khatam Al Anbia Hospital, Tehran, Iran
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24
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Recent advances in the anti-HCV mechanisms of interferon. Acta Pharm Sin B 2014; 4:241-7. [PMID: 26579391 PMCID: PMC4629091 DOI: 10.1016/j.apsb.2014.06.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 06/03/2014] [Accepted: 06/18/2014] [Indexed: 12/14/2022] Open
Abstract
Interferon (IFN) in combination with ribavirin has been the standard of care (SOC) for chronic hepatitis C for the past few decades. Although the current SOC lacks the desired efficacy, and 4 new direct-acting antiviral agents have been recently approved, interferons are still likely to remain the cornerstone of therapy for some time. Moreover, as an important cytokine system of innate immunity, host interferon signaling provides a powerful antiviral response. Nevertheless, the mechanisms by which HCV infection controls interferon production, and how interferons, in turn, trigger anti-HCV activities as well as control the outcome of HCV infection remain to be clarified. In this report, we review current progress in understanding the mechanisms of IFN against HCV, and also summarize the knowledge of induction of interferon signaling by HCV infection.
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Key Words
- Antiviral agent
- CHC, chronic hepatitis C
- DCs, dendritic cells
- DNAM1, DNAX accessory molecule-1
- E2, envelop 2
- GAS, IFN-γ-activated site
- GWAS, genome-wide association studies
- Hepatitis C virus
- IFN, interferon
- IFN-α, interferon-α
- IFNAR1, interferon-alpha receptor 1
- IFNAR2, interferon-alpha receptor 2
- IFNGR1, interferon gamma receptor 1
- IFNGR2, interferon gamma receptor 2
- IFNL4, IFN-lambda 4
- IL-10R2, interleukin-10 receptor 2
- IL-29, interleukin-29
- IRF-3, interferon regulatory factor 3
- IRGs, IFN regulatory genes
- ISG15, interferon-stimulated gene 15
- ISGF3, IFN-stimulated gene factor 3
- ISGs, IFN-stimulated genes
- ISREs, IFN-stimulated response elements
- Interferon
- JAKs, Janus activated kinases
- MAVS, mitochondrial antiviral signaling protein
- MDA-5, melanoma differentiation-associated gene-5
- MHC, major histocompatibility complex
- Molecular mechanism
- NKCs, natural killer cells
- NKTCs, natural killer T cells
- OAS, 2′-5′-oligoadenylate synthetase
- PAMPs, pathogen-associated molecular patterns
- PBMCs, peripheral blood mononuclear cells
- PKR, protein kinase R
- PRRs, pattern recognition receptors
- RIG-I, retinoic acid-inducible gene-I
- RLRs, RIG-I-like receptors
- RdRp, RNA dependent RNA polymerase
- SNPs, single-nucleotide polymorphisms
- SOC, standard of care
- STAT1, signal transducer and activator of transcription 1
- STAT2, signal transducer and activator of transcription 2
- SVR, sustained virological response
- TH1, T-helper-1
- TH2, T-helper-2
- TLRs, Toll-like receptors
- TYK2, tyrosine kinase 2
- USP18, ubiquitin specific peptidase 18
- dsRNA, double-stranded RNA
- pDC, plasmacytoid dendritic cell
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25
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Type III interferon attenuates a vesicular stomatitis virus-based vaccine vector. J Virol 2014; 88:10909-17. [PMID: 25008938 DOI: 10.1128/jvi.01910-14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
UNLABELLED Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities. However, IFN-λ signals through a distinct receptor complex that is expressed in a cell type-specific manner, which restricts its activity to epithelial barriers, particularly those corresponding to the respiratory and gastrointestinal tracts. In this study, we determined how IFN-λ expression from recombinant VSV would influence vector replication, spread, and immunogenicity. We demonstrate that IFN-λ expression severely attenuates VSV in cell culture. In vivo, IFN-λ limits VSV replication in the mouse lung after intranasal administration and reduces virus spread to other organs. Despite this attenuation, however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization. These findings demonstrate a novel method of viral vector attenuation that could be used in both vaccine and oncolytic virus applications. IMPORTANCE Viruses such as VSV that are used as vaccine vectors can induce protective T cell and antibody responses after a single dose. Additionally, IFN-λ is a potent antiviral agent that has certain advantages for clinical use compared to IFN-α/β, such as fewer patient side effects. Here, we demonstrate that IFN-λ attenuates VSV replication and spread following intranasal virus delivery but does not reduce the ability of VSV to induce potent protective immune responses. These findings demonstrate that the type III IFN family may have widespread applicability for improving the safety and efficacy of viral vaccine and oncolytic vectors.
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Durbin RK, Kotenko SV, Durbin JE. Interferon induction and function at the mucosal surface. Immunol Rev 2014; 255:25-39. [PMID: 23947345 DOI: 10.1111/imr.12101] [Citation(s) in RCA: 168] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Interferons (IFNs) are produced in response to virus infection and induce an antiviral state in virtually all cell types. In addition to upregulating the transcription of genes that inhibit virus replication, type I (or -α/β) IFNs also act to orchestrate the adaptive immune response to virus infection. Recently a new family of antiviral cytokines, the type III (or -λ) IFNs, has been identified that activate the same antiviral pathways via a distinct receptor. Although the identical transcription factor, IFN-stimulated gene factor 3 is activated by either IFN-α/β or IFN-λ signaling, differences in the induction and action of these two cytokine families are beginning to be appreciated. In this article, we review this emerging body of literature on the differing roles these cytokines play in host defense of the mucosal surface. Although many viruses enter the body through the respiratory and gastrointestinal tracts, we have focused the discussion on influenza A virus, respiratory syncytial virus, and rotavirus, three ubiquitous human pathogens that target the epithelial lining and are associated with a major disease burden.
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Affiliation(s)
- Russell K Durbin
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
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27
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Misumi I, Whitmire JK. IFN-λ exerts opposing effects on T cell responses depending on the chronicity of the virus infection. THE JOURNAL OF IMMUNOLOGY 2014; 192:3596-606. [PMID: 24646741 DOI: 10.4049/jimmunol.1301705] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
IFN-λ induces an antiviral state in many cell types and may contribute to the overall inflammatory environment after infection. Either of these effects may influence adaptive immune responses, but the role of type 3 IFNs in the development of primary and memory T cell responses to infection has not been evaluated. In this study, we examined T cell responses to acute or persistent lymphocytic choriomeningitis virus infection in IFN-λR1-deficient mice. Following acute infection, we find that IFN-λR1-deficient mice produced normal levels of IFN, robust NK cell responses, but greater than normal CD4+ and CD8+ T cell responses compared with wild type BALB/c mice. There were more T cells that were IL-7R(hi) and, correspondingly, the IFN-λR-deficient mice showed a 2- to 3-fold increase in memory T cell number. The inhibitory effect of IFN-λR expression was independent of direct cytokine signaling into T cells. In contrast with acute infection, the IFN-λR-deficient mice generated markedly diminished T cell responses and had greater weight loss compared with wild type mice when confronted with a highly disseminating variant of lymphocytic choriomeningitis virus. These data indicate that IFN-λR limits T cell responses and memory after transient infection but augments T cell responses during persisting infection. Thus, the immune-regulatory functions for IFN-λR are complex and vary with the overall inflammatory environment.
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Affiliation(s)
- Ichiro Misumi
- Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599
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28
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Youssef SS, Abbas EAER, Mostafa A, el Zanaty T, Seif SM. Association of IL28B polymorphism with fibrosis, liver inflammation, gender respective natural history of hepatitis C virus in Egyptian patients with genotype 4. J Interferon Cytokine Res 2014; 34:22-7. [PMID: 23981065 DOI: 10.1089/jir.2013.0036] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The polymorphism of interleukin 28B (IL28B) rs12979860 is associated with spontaneous and treatment-induced clearance in hepatitis C virus (HCV) genotype 4 (G4). However, there is no information on its interaction with gender, moreover its association with intrahepatic inflammation in North Africans is not studied and its association with fibrosis in North Africans (especially Egyptians) is controversial. This study aims to explore the association between the minor allele of the IL28B rs12979860 polymorphism with gender, fibrosis and necroinflammation in Egyptian G4 HCV patients. IL28B rs12979860 was genotyped in 224 individuals, including 100 healthy controls and 124 consecutive patients with chronic HCV. Results showed (1) IL28B rs12979860 minor alleles associated with susceptibity to chronic HCV mainly in men not women, (2) no association between IL28B rs12979860 with fibrosis and necroinflammation activity, (3) the IL28B rs12979860 TT genotype associated with severe fibrosis in women only and with the necroinflammation activity in men using a recessive model. In conclusion, the IL28B rs12979860 polymorphism is not associated with fibrosis and liver inflammation in Egyptian HCV G4. Nonetheless, the TT genotype of IL28B rs12979860 polymorphism affects the natural history of each gender independently.
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Affiliation(s)
- Samar Samir Youssef
- 1 Microbial Biotechnology Department, National Research Center , Cairo, Egypt
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29
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HIV-1 Env DNA vaccine plus protein boost delivered by EP expands B- and T-cell responses and neutralizing phenotype in vivo. PLoS One 2013; 8:e84234. [PMID: 24391921 PMCID: PMC3877240 DOI: 10.1371/journal.pone.0084234] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 11/13/2013] [Indexed: 02/07/2023] Open
Abstract
An effective HIV vaccine will most likely require the induction of strong T-cell responses, broadly neutralizing antibodies (bNAbs), and the elicitation of antibody-dependent cellular cytotoxicity (ADCC). Previously, we demonstrated the induction of strong HIV/SIV cellular immune responses in macaques and humans using synthetic consensus DNA immunogens delivered via adaptive electroporation (EP). However, the ability of this improved DNA approach to prime for relevant antibody responses has not been previously studied. Here, we investigate the immunogenicity of consensus DNA constructs encoding gp140 sequences from HIV-1 subtypes A, B, C and D in a DNA prime-protein boost vaccine regimen. Mice and guinea pigs were primed with single- and multi-clade DNA via EP and boosted with recombinant gp120 protein. Sera were analyzed for gp120 binding and induction of neutralizing antibody activity. Immunization with recombinant Env protein alone induced low-titer binding antibodies with limited neutralization breath. In contrast, the synthetic DNA prime-protein boost protocol induced significantly higher antibody binding titers. Furthermore, sera from DNA prime-protein boost groups were able to neutralize a broader range of viruses in a panel of tier 1 clade B viruses as well as multiple tier 1 clade A and clade C viruses. Further investigation of synthetic DNA prime plus adaptive EP plus protein boost appears warranted.
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30
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Villarreal DO, Talbott KT, Choo DK, Shedlock DJ, Weiner DB. Synthetic DNA vaccine strategies against persistent viral infections. Expert Rev Vaccines 2013; 12:537-54. [PMID: 23659301 DOI: 10.1586/erv.13.33] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The human body has developed an elaborate defense system against microbial pathogens and foreign antigens. However, particular microbes have evolved sophisticated mechanisms to evade immune surveillance, allowing persistence within the human host. In an effort to combat such infections, intensive research has focused on the development of effective prophylactic and therapeutic countermeasures to suppress or clear persistent viral infections. To date, popular therapeutic strategies have included the use of live-attenuated microbes, viral vectors and dendritic-cell vaccines aiming to help suppress or clear infection. In recent years, improved DNA vaccines have now re-emerged as a promising candidate for therapeutic intervention due to the development of advanced optimization and delivery technologies. For instance, genetic optimization of synthetic plasmid constructs and their encoded antigens, in vivo electroporation-mediated vaccine delivery, as well as codelivery with molecular adjuvants have collectively enhanced both transgene expression and the elicitation of vaccine-induced immunity. In addition, the development of potent heterologous prime-boost regimens has also provided significant contributions to DNA vaccine immunogenicity. Herein, the authors will focus on these recent improvements to this synthetic platform in relation to their application in combating persistent virus infection.
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Affiliation(s)
- Daniel O Villarreal
- University of Pennsylvania, Perelman School of Medicine, Department of Pathology & Laboratory Medicine, Philadelphia, PA 19104, USA
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31
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Muthumani K, Flingai S, Wise M, Tingey C, Ugen KE, Weiner DB. Optimized and enhanced DNA plasmid vector based in vivo construction of a neutralizing anti-HIV-1 envelope glycoprotein Fab. Hum Vaccin Immunother 2013; 9:2253-62. [PMID: 24045230 DOI: 10.4161/hv.26498] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Monoclonal antibody preparations have demonstrated considerable clinical utility in the treatment of specific malignancies, as well as inflammatory and infectious diseases. Antibodies are conventionally delivered by passive administration, typically requiring costly large-scale laboratory development and production. Additional limitations include the necessity for repeat administrations, and the length of in vivo potency. Therefore, the development of methods to generate therapeutic antibodies and antibody like molecules in vivo, distinct from an active antigen-based immunization strategy, would have considerable clinical utility. In fact, adeno-associated viral (AAV) vector mediated delivery of immunoglobulin genes with subsequent generation of functional antibodies has recently been developed. As well, anon-viral vector mediated nucleic acid based delivery technology could permit the generation of therapeutic/prophylactic antibodies in vivo, obviating potential safety issues associated with viral vector based gene delivery. This delivery strategy has limitations as well, mainly due to very low in vivo production and expression of protein from the delivered gene. In the study reported here we have constructed an "enhanced and optimized" DNA plasmid technology to generate immunoglobulin heavy and light chains (i.e., Fab fragments) from an established neutralizing anti-HIV envelope glycoprotein monoclonal antibody (VRC01). This "enhanced" DNA (E-DNA) plasmid technology includes codon/RNA optimization, leader sequence utilization, as well as targeted potentiation of delivery and expression of the Fab immunoglobulin genes through use of "adaptive" in vivo electroporation. The results demonstrate that delivery by this method of a single administration of the optimized Fab expressing constructs resulted in generation of Fab molecules in mouse sera possessing high antigen specific binding and HIV neutralization activity for at least 7 d after injection, against diverse HIV isolates. Importantly, this delivery strategy resulted in a rapid increase (i.e., in as little as 48 h) in Fab levels when compared with protein-based immunization. The active generation of functional Fab molecules in vivo has important conceptual and practical advantages over conventional ex vivo generation, purification and passive delivery of biologically active antibodies. Further study of this technique for the rapid generation and delivery of immunoglobulin and immunoglobulin like molecules is highly relevant and timely.
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Affiliation(s)
- Kar Muthumani
- Department of Pathology and Laboratory Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA
| | - Seleeke Flingai
- Department of Pathology and Laboratory Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA
| | - Megan Wise
- Department of Pathology and Laboratory Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA
| | - Colleen Tingey
- Department of Pathology and Laboratory Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA
| | - Kenneth E Ugen
- Department of Molecular Medicine; University of South Florida Morsani College of Medicine; Tampa, FL USA; Center for Molecular Delivery; University of South Florida; Tampa, FL USA
| | - David B Weiner
- Department of Pathology and Laboratory Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA
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32
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Asahina Y, Nakagawa M, Kakinuma S, Watanabe M. Polymorphism Near the Interleukin-28B Gene and Anti-Hepatitis C Viral Response. J Clin Transl Hepatol 2013; 1:39-44. [PMID: 26357605 PMCID: PMC4521272 DOI: 10.14218/jcth.2013.005xx] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 05/15/2013] [Accepted: 05/17/2013] [Indexed: 12/14/2022] Open
Abstract
In a recent genome-wide association study, single nucleotide polymorphisms (SNPs) located near the interleukin-28B gene (IL28B), which encodes type III interferon (IFN) λ3, were shown to be strongly associated with a viral response to pegylated IFNα (PEG-IFNα) and ribavirin (RBV) combination therapy and spontaneous viral clearance in patients chronically and acutely infected with hepatitis C virus (HCV), respectively. The global distribution of allele frequencies shows a remarkable pattern, in which a favorable allele is nearly fixed in East Asia, has an intermediate frequency in Europe, and is least frequent in Africa. Although the underlying mechanisms responsible for viral responses associated with IL28B SNPs have not been completely elucidated, IFN-stimulated gene expression in patients with unfavorable IL28B genotypes tends to be high at baseline and is insufficiently induced by exogenous IFN administration, resulting in poor treatment outcomes. Clinically, triple therapy with PEG-IFNα/RBV together with direct-acting antiviral agents (DAAs) is currently used to treat chronic hepatitis C as a first-line therapy. Although the predictive power of IL28B status may be attenuated, the IL28B genotype will remain relevant to the outcomes of DAA therapy when used in combination with PEG-IFNα as a backbone. Even with the introduction of IFN-free therapies with a new class of highly effective DAAs, IL28B SNPs are still useful predictors of treatment outcomes and can be used to individualize treatment strategies to maximize cost-effectiveness and identify patients at risk of being refractory to treatment. This review summarizes the current understanding of the clinical significance and role of IL28B in HCV infection and response to therapy.
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Affiliation(s)
- Yasuhiro Asahina
- Department of Gastroenterology and Hepatology
- Department of Liver Disease Control, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | | | - Sei Kakinuma
- Department of Gastroenterology and Hepatology
- Department of Liver Disease Control, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
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33
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Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, Giffear M, Pankhong P, Khan AS, Broderick KE, Knott C, Lin F, Boyer JD, Draghia-Akli R, White CJ, Kim JJ, Weiner DB, Sardesai NY. Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med 2013; 4:155ra138. [PMID: 23052295 DOI: 10.1126/scitranslmed.3004414] [Citation(s) in RCA: 239] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.
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Affiliation(s)
- Mark L Bagarazzi
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Jian Yan
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Matthew P Morrow
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Xuefei Shen
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - R Lamar Parker
- Lyndhurst Clinical Research, Winston-Salem, NC 27103, USA
| | - Jessica C Lee
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Mary Giffear
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Panyupa Pankhong
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Amir S Khan
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Kate E Broderick
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Christine Knott
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Feng Lin
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - Jean D Boyer
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ruxandra Draghia-Akli
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - C Jo White
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - J Joseph Kim
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
| | - David B Weiner
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Niranjan Y Sardesai
- Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA
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Bes M, Sauleda S, Campos-Varela I, Rodriguez-Frias F, Casamitjana N, Homs M, Piron M, Quer J, Tabernero D, Guardia J, Puig L, Esteban JI. IL28B genetic variation and hepatitis C virus-specific CD4(+) T-cell responses in anti-HCV-positive blood donors. J Viral Hepat 2012; 19:867-871. [PMID: 23121365 DOI: 10.1111/j.1365-2893.2012.01631.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Epidemiological, viral and host factors are associated with the outcome of hepatitis C virus (HCV) infection, and strong host immune responses against HCV favour viral clearance. Recently, genome-wide association studies have shown a strong correlation between single-nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene and spontaneous or treatment-induced HCV clearance. We have investigated whether protective IL28B genetic variants are associated with HCV-specific T-cell responses among Spanish blood donors. The rs12979860 IL28B haplotype was determined in 69 anti-HCV-positive blood donors (21 HCV RNA negative and 48 HCV RNA positive) and 30 seronegative donors. In all cases, HCV-specific CD4(+) T-cell responses to HCV recombinant proteins (core, NS3 and NS3 helicase) were assessed by ex vivo interferon-γ ELISpot assay. The rs12979860-CC genotype was highly overrepresented in donors with spontaneous HCV clearance when compared to those with chronic infection (76.2%vs 29.2%, P < 0.001; odds ratio, 7.77; 95% confidence interval, 2.4-25.3, P < 0.001). HCV-specific CD4(+) T-cell responses were detected in 16 (76.2%) spontaneous resolvers especially towards nonstructural proteins, but with no correlation with IL28B genotype. Chronic individuals had a significantly lower overall T-cell response again irrespective of IL28B genotype. When spontaneous resolvers and chronic individuals were stratified according to their IL28B genotype, significantly stronger T-cell responses were only observed among those with non-CC haplotypes. Although the protective rs12979860 IL28B CC genotype is associated with spontaneous HCV clearance, stronger CD4(+) T-cell responses towards NS3 were only evident among those with non-CC haplotypes.
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Affiliation(s)
- M Bes
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
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Zheng YW, Li H, Yu JP, Zhao H, Wang SE, Ren XB. Interferon-λs: special immunomodulatory agents and potential therapeutic targets. J Innate Immun 2012; 5:209-18. [PMID: 23207147 PMCID: PMC6741515 DOI: 10.1159/000345365] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Revised: 10/24/2012] [Accepted: 10/24/2012] [Indexed: 12/19/2022] Open
Abstract
Interferon (IFN)-λs are a new addition to the old IFN family and share many similarities, such as antiviral and antiproliferative characteristics, with type I IFNs. IFN-λs also exhibit unique characteristics in immunomodulation. Accumulating studies have indicated the interactions between IFN-λs and immune cells, which lead to the regulation of the latter. IFN-λs can influence dendritic cells (DCs) and their product, IFN-λs-DCs, can then regulate the function of T cells. On the other hand, IFN-λs can also directly affect T cells through inhibition of the T helper 2 cell (Th2) responses. IFN-λs have varying immunomodulatory functions under different physiological conditions or in different organs and can inhibit tumor growth via regulation of the immune system. Diseases associated with IFN-λs include asthma, allergy, and systemic lupus erythematosus. In this review, we summarize the current knowledge of the biology of IFN-λs and their immunomodulatory function in relevant human diseases.
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Affiliation(s)
- Ya-wen Zheng
- Department of Biotherapy, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Hui Li
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jin-pu Yu
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Hua Zhao
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Shizhen Emily Wang
- Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, Calif., USA
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Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol 2012; 57:1110-25. [PMID: 22659520 DOI: 10.1016/j.jhep.2012.05.016] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 05/11/2012] [Accepted: 05/14/2012] [Indexed: 12/20/2022]
Abstract
HCV infection is a global health problem that affects 170 million people worldwide. The severity of the disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Recently, the standard of care for genotype 1 patients has greatly improved with the addition of protease inhibitors (telaprevir or boceprevir) to pegylated interferon (PegIFN) and ribavirin (RBV). The prediction of fibrosis progression and the response to antiviral treatment are two major issues in the management of patients with chronic hepatitis C. Differential expression of mRNAs was first analyzed for both progression of fibrosis and treatment response. Specific polymorphisms, associated with either fibrosis or viral response, were identified thanks to major improvements in genome scanning technologies. Since 2009, several independent genome wide association studies (GWAS) have reported an association between genetic polymorphisms within the IL-28B promoter and both natural and treatment-induced clearance in genotype 1 infected patients. These different studies showed the strong association and the importance of IL-28B polymorphisms in the treatment response. Combining the different genetic factors could improve their predictive value and help identify patients at a high risk of progression of fibrosis as well as those with a lower chance of responding to treatment. The aim of this review was to discuss the genomic factors (mRNAs, miRNAs, and SNPs) and HCV infection with clinical implications for either progression of fibrosis or treatment response. Recent findings on the IL-28B polymorphism and its application in clinical practice will also be discussed.
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Affiliation(s)
- Emilie Estrabaud
- INSERM, UMR773, Team Viral hepatitis, Centre de Recherche Bichat Beaujon, BP 416, F-75018 Paris, France.
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Lebrec HN. Regulatory forum opinion piece*: immunotoxicology assessments in nonhuman primates--challenges and opportunities. Toxicol Pathol 2012; 41:548-51. [PMID: 22886347 DOI: 10.1177/0192623312455526] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The immune system has been recognized for decades as a potential "target organ" of toxicity. Immune system activation can result in cytokine release resulting in severe systemic toxicity. Immunosuppression can result in impaired host defense and an increase in opportunistic infection, reemergence of latent infection, poor responses to vaccination, or increased risk of certain cancers. Several regulatory documents have addressed various aspects of immunotoxicity assessments. Nonhuman primates (NHPs) and in particular macaques are often the only relevant species for biotechnology-derived investigational new drugs based on cross-reactivity with human and NHP targets. This article reviews the challenges and opportunities associated with monitoring immune function in NHPs in the context of regulatory expectations. The article emphasizes how a comprehensive assessment of immunotoxicity remains a challenge due to interanimal variability associated with certain parameters (e.g., T-dependent antibody response)and it identifies gaps, such as the stage of development of certain assays (e.g., cytotoxic T-cell function). Despite these challenges, a thorough assessment of target biology-driven theoretical risks, in combination with proper integration of all information from the standard toxicology studies, and the refinement of certain assays should enable proper risk assessment. To this effect, emphasis should be placed on leveraging predictive in vitro assays using human cells.
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Hayes CN, Imamura M, Aikata H, Chayama K. Genetics of IL28B and HCV--response to infection and treatment. Nat Rev Gastroenterol Hepatol 2012; 9:406-17. [PMID: 22641049 DOI: 10.1038/nrgastro.2012.101] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The IL28B locus attracted the attention of HCV researchers after a series of genome-wide association studies independently identified a strong association between common IL28B polymorphisms and the outcome of PEG-IFN-α plus ribavirin combination therapy in patients chronically infected with HCV genotype 1. This association was subsequently replicated for other HCV genotypes and has been linked to spontaneous eradication of HCV, development of steatosis and biochemical changes (such as altered levels of γ-glutamyl transpeptidase and LDL). Despite the introduction of direct-acting antiviral drugs, IL28B genetics are likely to play a part in patient selection and treatment decisions-moving towards a personalized approach to therapy. In HCV-infected patients with the so-called favourable IL28B genotype (rs12979860 CC; associated with better treatment response), hepatic expression levels of IL28B and interferon-stimulated genes seem to be reduced at baseline, but are induced more strongly after IFN-α administration, perhaps resulting in more effective elimination of the virus. Clarification of the mechanisms underlying these biological phenomena will lead to improved understanding of the antiviral effects of IFN-λ and, ideally, to the development of better therapies against HCV infection. This Review summarizes current understanding of the role of IL28B in HCV infection and response to therapy.
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Affiliation(s)
- C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku Hiroshima 734-8551, Japan
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Abstract
Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-gamma-inducible CXC chemokine ligand (CXCL)-9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases--mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes--are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process.
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Mohan M, Kaushal D, Aye PP, Alvarez X, Veazey RS, Lackner AA. Focused examination of the intestinal lamina propria yields greater molecular insight into mechanisms underlying SIV induced immune dysfunction. PLoS One 2012; 7:e34561. [PMID: 22511950 PMCID: PMC3325268 DOI: 10.1371/journal.pone.0034561] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Accepted: 03/05/2012] [Indexed: 12/12/2022] Open
Abstract
Background The Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4+ T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression. Methodology/Principal Findings To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). More importantly we maximized information gathering by examining distinct mucosal components (intraepithelial lymphocytes, lamina propria leukocytes [LPL], epithelium and fibrovascular stroma) separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase (±1.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, transcription and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1, CDK6, Gelsolin, Moesin) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFNγ3 (anti-HIV/viral), activation induced cytidine deaminase (B-cell function) and approximately 57 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3), immune activation (CD38, semaphorin7A, CD109), B-cell dysfunction (CD70), intestinal microbial translocation (Lipopolysaccharide binding protein) and mitochondrial antiviral signaling (NLRX1) genes. Reduced expression of CD28, CD4, CD86, CD93, NFATc1 (T-cells), TLR8, IL8, CCL18, DECTIN1 (macrophages), HLA-DOA and GPR183 (B-cells) at 90d PI suggests further deterioration of overall immune function. Conclusions/Significance The reported transcriptional signatures provide significant new details on the molecular pathology of HIV/SIV induced GI disease and provide new opportunity for future investigation.
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Affiliation(s)
- Mahesh Mohan
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Deepak Kaushal
- Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Pyone P. Aye
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Xavier Alvarez
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Ronald S. Veazey
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
| | - Andrew A. Lackner
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America
- * E-mail:
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Shin TH, Pankhong P, Yan J, Khan AS, Sardesai NY, Weiner DB. Induction of robust cellular immunity against HPV6 and HPV11 in mice by DNA vaccine encoding for E6/E7 antigen. Hum Vaccin Immunother 2012; 8:470-8. [PMID: 22336879 DOI: 10.4161/hv.19180] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Due to the strong relationship between the Human Papillomavirus (HPV) "high-risk" subtypes and cervical cancers, most HPV-related studies have been focusing on the "high-risk" HPV subtypes 16 and 18. However, it has been suggested that the "low-risk" subtypes of HPV, HPV6 and HPV11, are the major cause of recurrent respiratory papillomatosis and genital warts. In addition, HPV 6 and 11 are also associated with otolaryngologic malignancies, carcinoma of the lung, tonsil, larynx and low-grade cervical lesions. Therefore, development of HPV therapeutic vaccines targeting on subtypes 6 and 11 E6 or E7 are in great need. In this report, we describe two novel engineered DNA vaccines that encode HPV 6 and 11 consensus E6/E7 fusion proteins (p6E6E7 and p11E6E7) by utilizing a multi-phase strategy. Briefly, after generating consensus sequences, several modifications were performed to increase the expression of both constructs, including codon/RNA optimization, addition of a Kozak sequence and a highly efficient leader sequence. An endoproteolytic cleavage site was also introduced between E6 and E7 protein for proper protein folding and for better CTL processing. The expressions of both constructs were confirmed by western blot analysis and immunofluorescence assay. Vaccination with these DNA vaccines could elicit robust cellular immune responses. The epitope mapping assay was performed to further characterize the cellular immune responses induced by p6E6E7 and p11E6E7. The HPV 6 and 11 E6 or E7-specific immunodominant and subdominant epitopes were verified, respectively. The intracellular cytokine staining revealed that the magnitude of IFN-γ and TNF-α secretion in antigen-specific CD8(+) cells was significantly enhanced, indicating that the immune responses elicited by p6E6E7 and p11E6E7 was heavily skewed toward driving CD8(+) T cells. Such DNA immunogens are interesting candidates for further studies on HPV 6 and 11-associated diseases.
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Affiliation(s)
- Thomas H Shin
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Bochud PY, Bibert S, Kutalik Z, Patin E, Guergnon J, Nalpas B, Goossens N, Kuske L, Müllhaupt B, Gerlach T, Heim MH, Moradpour D, Cerny A, Malinverni R, Regenass S, Dollenmaier G, Hirsch H, Martinetti G, Gorgiewski M, Bourlière M, Poynard T, Theodorou I, Abel L, Pol S, Dufour JF, Negro F. IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes. Hepatology 2012; 55:384-94. [PMID: 22180014 DOI: 10.1002/hep.24678] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 08/30/2011] [Indexed: 12/15/2022]
Abstract
UNLABELLED Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917-previously shown to be at risk of treatment failure-was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma. CONCLUSION In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes.
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Affiliation(s)
- Pierre-Yves Bochud
- Service of Infectious Diseases, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
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Ferraro B, Morrow MP, Hutnick NA, Shin TH, Lucke CE, Weiner DB. Clinical applications of DNA vaccines: current progress. Clin Infect Dis 2011; 53:296-302. [PMID: 21765081 DOI: 10.1093/cid/cir334] [Citation(s) in RCA: 264] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
It was discovered almost 20 years ago that plasmid DNA, when injected into the skin or muscle of mice, could induce immune responses to encoded antigens. Since that time, there has since been much progress in understanding the basic biology behind this deceptively simple vaccine platform and much technological advancement to enhance immune potency. Among these advancements are improved formulations and improved physical methods of delivery, which increase the uptake of vaccine plasmids by cells; optimization of vaccine vectors and encoded antigens; and the development of novel formulations and adjuvants to augment and direct the host immune response. The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas. This review focuses on these advances and discusses both preventive and immunotherapeutic clinical applications.
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Affiliation(s)
- Bernadette Ferraro
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Abstract
For decades, type I IFNs have been considered indispensable and unique antiviral mediators for the activation of rapid innate antiviral protection. However, the recent discovery of type III IFNs is challenging this paradigm. Since their identification in 2002/2003 by two independent groups, type III IFNs or IFN-λs, also known as IL-28/29, have been the subject of increased study with consequent recognition of their importance in virology and immunology. Initial reports suggested that IFN-λs functionally resemble type I IFNs. Although IFN-λs and classical type I IFNs (IFN-α/β) utilize distinct receptor complexes for signaling, both types of IFNs activate similar intracellular signaling pathways and biological activities, including the ability to induce antiviral state in cells, and both type I and type III IFNs are induced by viral infection. However, different antiviral potency, pattern of their induction and differential tissue expression of their corresponding receptor subunits suggest that the type I and type III IFN antiviral systems do not merely duplicate each other. Recent studies have started to reveal unique biological activities of IFN-λs in and beyond innate antiviral immunity.
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Affiliation(s)
- Sergei V Kotenko
- Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, New Jersey Medical School, University of Medicine and Dentistry, USA.
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Immune modulation through 4-1BB enhances SIV vaccine protection in non-human primates against SIVmac251 challenge. PLoS One 2011; 6:e24250. [PMID: 21935390 PMCID: PMC3174159 DOI: 10.1371/journal.pone.0024250] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 08/05/2011] [Indexed: 01/22/2023] Open
Abstract
Costimulatory molecules play a central role in the development of cellular immunity. Understanding how costimulatory pathways can be directed to positively influence the immune response may be critical for the generation of an effective HIV vaccine. Here, we evaluated the ability of intravenous administration of a blocking monoclonal antibody (mAb) directed against the negative costimulatory molecule CTLA-4, and an agonist mAb directed against the positive costimulatory molecule 4-1BB, either alone or in combination, to augment intramuscular SIV DNA immunizations. We then tested the ability these of these responses to impact a high-dose SIVmac251 challenge. Following immunization, the groups infused with the anti-4-1BB mAb exhibited enhanced IFN-γ responses compared to the DNA vaccine only group. Interestingly, although CTLA-4 blockade alone did not enhance IFN-γ responses it did increase the proliferative capacity of the CD4+ and CD8+ T cells. The combination of both mAbs enhanced the magnitude of the polyfunctional CD8+ T cell response. Following challenge, the group that received both mAbs exhibited a significant, ∼2.0 log, decrease in plasma viral load compared to the naïve group the included complete suppression of viral load in some animals. Furthermore, the use of the CTLA-4 blocking antibody resulted in significantly higher viral loads during chronic infection compared to animals that received the 4-1BB mAb, likely due to the higher CD4+ T cell proliferative responses which were driven by this adjuvant following immunization. These novel studies show that these adjuvants induce differential modulation of immune responses, which have dramatically different consequences for control of SIV replication, suggesting important implications for HIV vaccine development.
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Abstract
For two decades the scientific community has sought to understand why some people clear hepatitis C virus (HCV) and others do not. Recently, several large genome-wide association studies have identified single nucleotide polymorphisms (SNPs) linked to interferon lambda 3 (IFNλ3) that are associated with the spontaneous resolution and successful treatment of HCV infection. These observations are generating intense research activity; the hope is that IFNλ3 genetic variants may serve as important predictive biomarkers of treatment outcome and offer new insights into the biological pathways involved in viral control. A pharmacogenomic treatment approach for HCV can now be envisaged, with the incorporation of host genetic variants into a predictive treatment algorithm with other factors. The SNPs associated with the clinical outcome of HCV infection are located some distance from the IFNλ3 gene itself, and causal genetic variants have yet to be clearly defined. Locating these causal variants, mapping in detail the IFNλ3 signalling pathways and determining the downstream genetic signature so induced will clarify the role of IFNλ3 in the pathogenesis of HCV. Clinical studies assessing safety and efficacy in the treatment of HCV with exogenous IFNλ3 are currently underway. Early results suggest that IFNλ3 treatment inhibits HCV replication and is associated with a limited side effect profile. However, hepatotoxicity in both healthy volunteers and HCV-infected patients has been described. This review discusses the genetic studies that link IFNλ3 to both the spontaneous resolution and treatment-induced clearance of HCV and the potential impact of this in clinical practice, the biology of IFNλ3 as currently understood and how this may impact on HCV infection, and describes the early studies that assess the role of this cytokine in the treatment of patients with HCV.
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Affiliation(s)
- Christabel Kelly
- Peter Medawar Building for Pathogen Research, Oxford NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, UK
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Schmidt J, Thimme R, Neumann-Haefelin C. Host genetics in immune-mediated hepatitis C virus clearance. Biomark Med 2011; 5:155-69. [PMID: 21473719 DOI: 10.2217/bmm.11.19] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Upon infection with hepatitis C virus (HCV), only few patients spontaneously clear the virus, while most patients develop chronic HCV infection. The host innate and adaptive immune response is believed to be the key determinant of viral clearance or persistence. Several host factors have been demonstrated to influence the efficiency of the antiviral immune response, including IL-28B polymorphisms, inhibitory natural killer cell receptors, as well as HLA class I and II alleles presenting viral antigens to CD8(+) and CD4(+) T cells. The understanding of the respective mechanisms is essential for the development of successful vaccination strategies against HCV.
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Affiliation(s)
- Julia Schmidt
- Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany
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Muthumani K, Shedlock DJ, Choo DK, Fagone P, Kawalekar OU, Goodman J, Bian CB, Ramanathan AA, Atman P, Tebas P, Chattergoon MA, Choo AY, Weiner DB. HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells. THE JOURNAL OF IMMUNOLOGY 2011; 187:2932-43. [PMID: 21856939 DOI: 10.4049/jimmunol.1100594] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death (PD)-1 on virus-specific CD8(+) T cells. PD-1 is induced upon T cell activation, and its prolonged expression facilitates CD8(+) T cell inhibitory signals when bound to its B7 family ligands, PD-ligand (L)1/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1/PD-L interaction by Abs may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1 in which virus-mediated upregulation induced a state of nonresponsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1, after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-γ, IL-2, and IL-12 upon restimulation. In addition, we identify a critical role for the PI3K/serine-threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.
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Affiliation(s)
- Karuppiah Muthumani
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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Holmes JA, Sievert W, Thompson AJ. IL28B polymorphism and genetic biomarkers of viral clearance in hepatitis C virus infection. Biomark Med 2011; 5:461-78. [PMID: 21861668 DOI: 10.2217/bmm.11.47] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Infection with hepatitis C virus (HCV) is a major global health issue. Only a small proportion of patients clear the virus spontaneously and the majority develop chronic hepatitis C infection. Chronic hepatitis C is one of the most common causes of advanced liver disease in the western world and is now the leading indication for liver transplantation. Unfortunately, the standard treatment, consisting of pegylated-interferon and ribavirin, is suboptimal. Less than 50% of patients infected with HCV genotype 1 are cured, treatment is costly and is associated with significant toxicity. Therefore, there has been a need to identify accurate predictors of treatment outcome to facilitate treatment decision-making. Four independent genome-wide association studies have recently confirmed an association between genetic variation in the region of the IL28B gene and treatment outcome in HCV-1 patients. Patients who carry the good response variant are two- to three-fold more likely to be cured. The difference in the frequency of the good response variant between patients of different ethnic background explains much of the recognized ethnic disparity in treatment response rates. The IL28B variants are also associated with likelihood of spontaneous clearance of HCV infection. This discovery represents a significant advance in our ability to personalize HCV therapy, as well as suggesting novel avenues for research into viral pathogenesis and therapeutic development.
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Affiliation(s)
- Jacinta A Holmes
- Department of Gastroenterology & Hepatology, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, Melbourne, Victoria 3065, Australia
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Luci C, Anjuère F. IFN-λs and BDCA3+/CD8α+ dendritic cells: towards the design of novel vaccine adjuvants? Expert Rev Vaccines 2011; 10:159-61. [PMID: 21332265 DOI: 10.1586/erv.10.168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
IFN-λs are related to type I interferons but their receptor has a more cell-restricted pattern of expression. Consequently, one can expect that IFN-λs have antiviral and anti-tumoral activities as well as immunomodulatory properties with less adverse side-effects than type I interferons. However, their roles in physiopathology and immunoregulation remain to be fully elucidated. The study under evaluation identifies that murine CD8α(+) dendritic cells and their recently described human equivalent, BDCA3(+) dendritic cells, are the major producers of IFN-λs in response to dsRNA poly I:C. This study illustrates a new function for a DC subset conserved between species. These findings may impact the development of vaccine or therapeutic strategies based on DC targeting.
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Affiliation(s)
- Carmelo Luci
- INSERM, UMR 634, Faculté de Médecine Pasteur, 28 Avenue de Valombrose, 06107 Nice cedex 2, France
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