Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.

Viruses have developed strategies to counteract signalling through Toll-like receptors (TLRs) that are involved in the detection of viruses and induction of proinflammatory cytokines and IFNs. Vaccinia virus (VACV) encodes A46 protein which disrupts TLR signalling by interfering with TLR: adaptor in...

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Autores principales:	Beatriz Perdiguero, Carmen Elena Gómez, Mauro Di Pilato, Carlos Oscar S Sorzano, Julie Delaloye, Thierry Roger, Thierry Calandra, Giuseppe Pantaleo, Mariano Esteban
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/50b23a8342ea410a883b5eff6aeb8174
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spelling	oai:doaj.org-article:50b23a8342ea410a883b5eff6aeb81742021-11-18T08:54:53ZDeletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.1932-620310.1371/journal.pone.0074831https://doaj.org/article/50b23a8342ea410a883b5eff6aeb81742013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24069354/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Viruses have developed strategies to counteract signalling through Toll-like receptors (TLRs) that are involved in the detection of viruses and induction of proinflammatory cytokines and IFNs. Vaccinia virus (VACV) encodes A46 protein which disrupts TLR signalling by interfering with TLR: adaptor interactions. Since the innate immune response to viruses is critical to induce protective immunity, we studied whether deletion of A46R gene in a NYVAC vector expressing HIV-1 Env, Gag, Pol and Nef antigens (NYVAC-C) improves immune responses against HIV-1 antigens. This question was examined in human macrophages and in mice infected with a single A46R deletion mutant of the vaccine candidate NYVAC-C (NYVAC-C-ΔA46R). The viral gene A46R is not required for virus replication in primary chicken embryo fibroblast (CEF) cells and its deletion in NYVAC-C markedly increases TNF, IL-6 and IL-8 secretion by human macrophages. Analysis of the immune responses elicited in BALB/c mice after DNA prime/NYVAC boost immunization shows that deletion of A46R improves the magnitude of the HIV-1-specific CD4 and CD8 T cell immune responses during adaptive and memory phases, maintains the functional profile observed with the parental NYVAC-C and enhances anti-gp120 humoral response during the memory phase. These findings establish the immunological role of VACV A46R on innate immune responses of macrophages in vitro and antigen-specific T and B cell immune responses in vivo and suggest that deletion of viral inhibitors of TLR signalling is a useful approach for the improvement of poxvirus-based vaccine candidates.Beatriz PerdigueroCarmen Elena GómezMauro Di PilatoCarlos Oscar S SorzanoJulie DelaloyeThierry RogerThierry CalandraGiuseppe PantaleoMariano EstebanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e74831 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Beatriz Perdiguero Carmen Elena Gómez Mauro Di Pilato Carlos Oscar S Sorzano Julie Delaloye Thierry Roger Thierry Calandra Giuseppe Pantaleo Mariano Esteban Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.
description	Viruses have developed strategies to counteract signalling through Toll-like receptors (TLRs) that are involved in the detection of viruses and induction of proinflammatory cytokines and IFNs. Vaccinia virus (VACV) encodes A46 protein which disrupts TLR signalling by interfering with TLR: adaptor interactions. Since the innate immune response to viruses is critical to induce protective immunity, we studied whether deletion of A46R gene in a NYVAC vector expressing HIV-1 Env, Gag, Pol and Nef antigens (NYVAC-C) improves immune responses against HIV-1 antigens. This question was examined in human macrophages and in mice infected with a single A46R deletion mutant of the vaccine candidate NYVAC-C (NYVAC-C-ΔA46R). The viral gene A46R is not required for virus replication in primary chicken embryo fibroblast (CEF) cells and its deletion in NYVAC-C markedly increases TNF, IL-6 and IL-8 secretion by human macrophages. Analysis of the immune responses elicited in BALB/c mice after DNA prime/NYVAC boost immunization shows that deletion of A46R improves the magnitude of the HIV-1-specific CD4 and CD8 T cell immune responses during adaptive and memory phases, maintains the functional profile observed with the parental NYVAC-C and enhances anti-gp120 humoral response during the memory phase. These findings establish the immunological role of VACV A46R on innate immune responses of macrophages in vitro and antigen-specific T and B cell immune responses in vivo and suggest that deletion of viral inhibitors of TLR signalling is a useful approach for the improvement of poxvirus-based vaccine candidates.
format	article
author	Beatriz Perdiguero Carmen Elena Gómez Mauro Di Pilato Carlos Oscar S Sorzano Julie Delaloye Thierry Roger Thierry Calandra Giuseppe Pantaleo Mariano Esteban
author_facet	Beatriz Perdiguero Carmen Elena Gómez Mauro Di Pilato Carlos Oscar S Sorzano Julie Delaloye Thierry Roger Thierry Calandra Giuseppe Pantaleo Mariano Esteban
author_sort	Beatriz Perdiguero
title	Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.
title_short	Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.
title_full	Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.
title_fullStr	Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.
title_full_unstemmed	Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.
title_sort	deletion of the vaccinia virus gene a46r, encoding for an inhibitor of tlr signalling, is an effective approach to enhance the immunogenicity in mice of the hiv/aids vaccine candidate nyvac-c.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/50b23a8342ea410a883b5eff6aeb8174
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Deletion of the vaccinia virus gene A46R, encoding for an inhibitor of TLR signalling, is an effective approach to enhance the immunogenicity in mice of the HIV/AIDS vaccine candidate NYVAC-C.

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