Improving Adaptive and Memory Immune Responses of an HIV/AIDS Vaccine Candidate MVA-B by Deletion of Vaccinia Virus Genes (C6L and K7R) Blocking Interferon Signaling Pathways
Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by...
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| description | Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates. |
| doi_str_mv | 10.1371/journal.pone.0066894 |
| format | Article |
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To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0066894</identifier><identifier>PMID: 23826170</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acquired immune deficiency syndrome ; Adaptive Immunity ; AIDS ; AIDS Vaccines - genetics ; AIDS Vaccines - immunology ; Animals ; Antigens ; Biology ; CD4 antigen ; CD8 antigen ; Cell Line ; Chemokines ; Chick Embryo ; Clonal deletion ; Cytokines ; Deletion mutant ; Dendritic cells ; Dendritic Cells - immunology ; Deoxyribonucleic acid ; DNA ; Durability ; Effector cells ; Female ; Gag protein ; Gene expression ; Genes ; Genetic Vectors ; HIV ; HIV Antibodies - metabolism ; HIV Antigens - genetics ; HIV-1 - genetics ; Human immunodeficiency virus ; Humans ; Immune response ; Immune response (cell-mediated) ; Immunity, Innate ; Immunization ; Immunogenicity ; Immunologic Memory ; Immunological memory ; Immunology ; Immunomodulation ; Innate immunity ; Interferon ; Interferon regulatory factor 3 ; Interferons - metabolism ; Lymphocytes ; Lymphocytes T ; Macrophages ; Macrophages - immunology ; Medicine ; Memory cells ; Mice, Inbred BALB C ; Monocytes ; Mutants ; Poxviridae - genetics ; Sequence Deletion ; Signal Transduction ; Signaling ; T-Lymphocytes - immunology ; Tumor necrosis factor-α ; Vaccines ; Vaccines, Synthetic - immunology ; Vaccinia virus - genetics ; Viral Proteins - genetics ; Viruses</subject><ispartof>PloS one, 2013-06, Vol.8 (6), p.e66894</ispartof><rights>2013 García-Arriaza et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 García-Arriaza et al 2013 García-Arriaza et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a60f88fdf111ab34537b604e461b8d03be8f5ae917b3efd5e7bc36b59ca874ec3</citedby><cites>FETCH-LOGICAL-c526t-a60f88fdf111ab34537b604e461b8d03be8f5ae917b3efd5e7bc36b59ca874ec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694958/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694958/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23826170$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lu, Shan</contributor><creatorcontrib>García-Arriaza, Juan</creatorcontrib><creatorcontrib>Arnáez, Pilar</creatorcontrib><creatorcontrib>Gómez, Carmen E</creatorcontrib><creatorcontrib>Sorzano, Carlos Óscar S</creatorcontrib><creatorcontrib>Esteban, Mariano</creatorcontrib><title>Improving Adaptive and Memory Immune Responses of an HIV/AIDS Vaccine Candidate MVA-B by Deletion of Vaccinia Virus Genes (C6L and K7R) Blocking Interferon Signaling Pathways</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.</description><subject>Acquired immune deficiency syndrome</subject><subject>Adaptive Immunity</subject><subject>AIDS</subject><subject>AIDS Vaccines - genetics</subject><subject>AIDS Vaccines - immunology</subject><subject>Animals</subject><subject>Antigens</subject><subject>Biology</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell Line</subject><subject>Chemokines</subject><subject>Chick Embryo</subject><subject>Clonal deletion</subject><subject>Cytokines</subject><subject>Deletion mutant</subject><subject>Dendritic cells</subject><subject>Dendritic Cells - immunology</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Durability</subject><subject>Effector cells</subject><subject>Female</subject><subject>Gag protein</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic Vectors</subject><subject>HIV</subject><subject>HIV Antibodies - metabolism</subject><subject>HIV Antigens - genetics</subject><subject>HIV-1 - genetics</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune response (cell-mediated)</subject><subject>Immunity, Innate</subject><subject>Immunization</subject><subject>Immunogenicity</subject><subject>Immunologic Memory</subject><subject>Immunological memory</subject><subject>Immunology</subject><subject>Immunomodulation</subject><subject>Innate immunity</subject><subject>Interferon</subject><subject>Interferon regulatory factor 3</subject><subject>Interferons - metabolism</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Macrophages - immunology</subject><subject>Medicine</subject><subject>Memory cells</subject><subject>Mice, Inbred BALB C</subject><subject>Monocytes</subject><subject>Mutants</subject><subject>Poxviridae - genetics</subject><subject>Sequence Deletion</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>T-Lymphocytes - immunology</subject><subject>Tumor necrosis factor-α</subject><subject>Vaccines</subject><subject>Vaccines, Synthetic - immunology</subject><subject>Vaccinia virus - genetics</subject><subject>Viral Proteins - genetics</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1ktFu0zAUhiMEYqPwBggscQMX6ew4cZKbSV0HW0Qn0Aa9tRz7uHNJ4mCnRX0pnhF3zabtgitbPv___cdHJ4reEjwlNCcna7txnWimve1gijFjRZk-i45JSZOYJZg-f3Q_il55v8Y4owVjL6OjhBYJIzk-jv5Wbe_s1nQrNFOiH8wWkOgUuoLWuh2q2nbTAboGH2I8eGR1KKPLankyq85v0FJIaYJgHjxGiQHQ1XIWn6F6h86hgcHYbm85yIxAS-M2Hl1AF1Af52xxl_U1v_6Ezhorf-3bqLoBnAYXnDdmFX64f_wuhts_YudfRy-0aDy8Gc9J9PPL5x_zy3jx7aKazxaxzBI2xIJhXRRaaUKIqGma0bxmOIWUkbpQmNZQ6ExASfKaglYZ5LWkrM5KKYo8BUkn0fsDt2-s5-OoPQ-DT0iSkjDYSVQdFMqKNe-daYXbcSsMv3uwbsWFG4xsgKuMijKASwE6lZgVKVClBNE0V7jGOrBOx7RN3YKS0A1ONE-gTyudueUru-WUlWmZFQHwYQQ4-3sDfvhPy-lBJZ313oF-SCB4ryP3Lr7fKT7uVLC9e9zdg-l-ieg_8HLL5g</recordid><startdate>20130627</startdate><enddate>20130627</enddate><creator>García-Arriaza, Juan</creator><creator>Arnáez, Pilar</creator><creator>Gómez, Carmen E</creator><creator>Sorzano, Carlos Óscar S</creator><creator>Esteban, Mariano</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130627</creationdate><title>Improving Adaptive and Memory Immune Responses of an HIV/AIDS Vaccine Candidate MVA-B by Deletion of Vaccinia Virus Genes (C6L and K7R) Blocking Interferon Signaling Pathways</title><author>García-Arriaza, Juan ; Arnáez, Pilar ; Gómez, Carmen E ; Sorzano, Carlos Óscar S ; Esteban, Mariano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-a60f88fdf111ab34537b604e461b8d03be8f5ae917b3efd5e7bc36b59ca874ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>Adaptive Immunity</topic><topic>AIDS</topic><topic>AIDS Vaccines - genetics</topic><topic>AIDS Vaccines - immunology</topic><topic>Animals</topic><topic>Antigens</topic><topic>Biology</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell Line</topic><topic>Chemokines</topic><topic>Chick Embryo</topic><topic>Clonal deletion</topic><topic>Cytokines</topic><topic>Deletion mutant</topic><topic>Dendritic cells</topic><topic>Dendritic Cells - immunology</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Durability</topic><topic>Effector cells</topic><topic>Female</topic><topic>Gag protein</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic Vectors</topic><topic>HIV</topic><topic>HIV Antibodies - metabolism</topic><topic>HIV Antigens - genetics</topic><topic>HIV-1 - genetics</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune response (cell-mediated)</topic><topic>Immunity, Innate</topic><topic>Immunization</topic><topic>Immunogenicity</topic><topic>Immunologic Memory</topic><topic>Immunological memory</topic><topic>Immunology</topic><topic>Immunomodulation</topic><topic>Innate immunity</topic><topic>Interferon</topic><topic>Interferon regulatory factor 3</topic><topic>Interferons - metabolism</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Macrophages - immunology</topic><topic>Medicine</topic><topic>Memory cells</topic><topic>Mice, Inbred BALB C</topic><topic>Monocytes</topic><topic>Mutants</topic><topic>Poxviridae - genetics</topic><topic>Sequence Deletion</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>T-Lymphocytes - immunology</topic><topic>Tumor necrosis factor-α</topic><topic>Vaccines</topic><topic>Vaccines, Synthetic - immunology</topic><topic>Vaccinia virus - genetics</topic><topic>Viral Proteins - genetics</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>García-Arriaza, Juan</creatorcontrib><creatorcontrib>Arnáez, Pilar</creatorcontrib><creatorcontrib>Gómez, Carmen E</creatorcontrib><creatorcontrib>Sorzano, Carlos Óscar S</creatorcontrib><creatorcontrib>Esteban, Mariano</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>García-Arriaza, Juan</au><au>Arnáez, Pilar</au><au>Gómez, Carmen E</au><au>Sorzano, Carlos Óscar S</au><au>Esteban, Mariano</au><au>Lu, Shan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Improving Adaptive and Memory Immune Responses of an HIV/AIDS Vaccine Candidate MVA-B by Deletion of Vaccinia Virus Genes (C6L and K7R) Blocking Interferon Signaling Pathways</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-06-27</date><risdate>2013</risdate><volume>8</volume><issue>6</issue><spage>e66894</spage><pages>e66894-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23826170</pmid><doi>10.1371/journal.pone.0066894</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-06, Vol.8 (6), p.e66894 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1372124119 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acquired immune deficiency syndrome Adaptive Immunity AIDS AIDS Vaccines - genetics AIDS Vaccines - immunology Animals Antigens Biology CD4 antigen CD8 antigen Cell Line Chemokines Chick Embryo Clonal deletion Cytokines Deletion mutant Dendritic cells Dendritic Cells - immunology Deoxyribonucleic acid DNA Durability Effector cells Female Gag protein Gene expression Genes Genetic Vectors HIV HIV Antibodies - metabolism HIV Antigens - genetics HIV-1 - genetics Human immunodeficiency virus Humans Immune response Immune response (cell-mediated) Immunity, Innate Immunization Immunogenicity Immunologic Memory Immunological memory Immunology Immunomodulation Innate immunity Interferon Interferon regulatory factor 3 Interferons - metabolism Lymphocytes Lymphocytes T Macrophages Macrophages - immunology Medicine Memory cells Mice, Inbred BALB C Monocytes Mutants Poxviridae - genetics Sequence Deletion Signal Transduction Signaling T-Lymphocytes - immunology Tumor necrosis factor-α Vaccines Vaccines, Synthetic - immunology Vaccinia virus - genetics Viral Proteins - genetics Viruses |
| title | Improving Adaptive and Memory Immune Responses of an HIV/AIDS Vaccine Candidate MVA-B by Deletion of Vaccinia Virus Genes (C6L and K7R) Blocking Interferon Signaling Pathways |
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