Back to Search
Start Over
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.
- Source :
-
PloS one [PLoS One] 2013 Sep 17; Vol. 8 (9), pp. e74831. Date of Electronic Publication: 2013 Sep 17 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Adaptive Immunity
Animals
HIV Envelope Protein gp120 immunology
HIV Infections prevention & control
HIV-1 immunology
Humans
Immunity, Humoral
Immunologic Memory
Interleukin-6 biosynthesis
Interleukin-8 biosynthesis
Macrophages immunology
Macrophages metabolism
Mice
Mutation
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
Tumor Necrosis Factors biosynthesis
AIDS Vaccines genetics
AIDS Vaccines immunology
Gene Deletion
Signal Transduction
Toll-Like Receptors metabolism
Vaccinia virus genetics
Viral Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24069354
- Full Text :
- https://doi.org/10.1371/journal.pone.0074831