Fragmentation of SIV-gag vaccine induces broader T cell responses.
High mutation rates of human immunodeficiency virus (HIV) allows escape from T cell recognition preventing development of effective T cell vaccines. Vaccines that induce diverse T cell immune responses would help overcome this problem. Using SIV gag as a model vaccine, we investigated two approaches...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3485275?pdf=render |
| _version_ | 1818566512065118208 |
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| author | Adel Benlahrech Andrea Meiser Shanthi Herath Timos Papagatsias Takis Athanasopoulos Fucheng Li Steve Self Veronique Bachy Catherine Hervouet Karen Logan Linda Klavinskis George Dickson Steven Patterson |
| author_facet | Adel Benlahrech Andrea Meiser Shanthi Herath Timos Papagatsias Takis Athanasopoulos Fucheng Li Steve Self Veronique Bachy Catherine Hervouet Karen Logan Linda Klavinskis George Dickson Steven Patterson |
| author_sort | Adel Benlahrech |
| collection | DOAJ |
| description | High mutation rates of human immunodeficiency virus (HIV) allows escape from T cell recognition preventing development of effective T cell vaccines. Vaccines that induce diverse T cell immune responses would help overcome this problem. Using SIV gag as a model vaccine, we investigated two approaches to increase the breadth of the CD8 T cell response. Namely, fusion of vaccine genes to ubiquitin to target the proteasome and increase levels of MHC class I peptide complexes and gene fragmentation to overcome competition between epitopes for presentation and recognition.three vaccines were compared: full-length unmodified SIV-mac239 gag, full-length gag fused at the N-terminus to ubiquitin and 7 gag fragments of equal size spanning the whole of gag with ubiquitin-fused to the N-terminus of each fragment. Genes were cloned into a replication defective adenovirus vector and immunogenicity assessed in an in vitro human priming system. The breadth of the CD8 T cell response, defined by the number of distinct epitopes, was assessed by IFN-γ-ELISPOT and memory phenotype and cytokine production evaluated by flow cytometry. We observed an increase of two- to six-fold in the number of epitopes recognised in the ubiquitin-fused fragments compared to the ubiquitin-fused full-length gag. In contrast, although proteasomal targeting was achieved, there was a marked reduction in the number of epitopes recognised in the ubiquitin-fused full-length gag compared to the full-length unmodified gene, but there were no differences in the number of epitope responses induced by non-ubiquitinated full-length gag and the ubiquitin-fused mini genes. Fragmentation and ubiquitination did not affect T cell memory differentiation and polyfunctionality, though most responses were directed against the Ad5 vector.Fragmentation but not fusion with ubiquitin increases the breadth of the CD8 T vaccine response against SIV-mac239 gag. Thus gene fragmentation of HIV vaccines may maximise responses. |
| first_indexed | 2024-12-14T01:54:38Z |
| format | Article |
| id | doaj.art-07d5304ebad441b4a2b5454abd05f3ee |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T01:54:38Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-07d5304ebad441b4a2b5454abd05f3ee2022-12-21T23:21:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4803810.1371/journal.pone.0048038Fragmentation of SIV-gag vaccine induces broader T cell responses.Adel BenlahrechAndrea MeiserShanthi HerathTimos PapagatsiasTakis AthanasopoulosFucheng LiSteve SelfVeronique BachyCatherine HervouetKaren LoganLinda KlavinskisGeorge DicksonSteven PattersonHigh mutation rates of human immunodeficiency virus (HIV) allows escape from T cell recognition preventing development of effective T cell vaccines. Vaccines that induce diverse T cell immune responses would help overcome this problem. Using SIV gag as a model vaccine, we investigated two approaches to increase the breadth of the CD8 T cell response. Namely, fusion of vaccine genes to ubiquitin to target the proteasome and increase levels of MHC class I peptide complexes and gene fragmentation to overcome competition between epitopes for presentation and recognition.three vaccines were compared: full-length unmodified SIV-mac239 gag, full-length gag fused at the N-terminus to ubiquitin and 7 gag fragments of equal size spanning the whole of gag with ubiquitin-fused to the N-terminus of each fragment. Genes were cloned into a replication defective adenovirus vector and immunogenicity assessed in an in vitro human priming system. The breadth of the CD8 T cell response, defined by the number of distinct epitopes, was assessed by IFN-γ-ELISPOT and memory phenotype and cytokine production evaluated by flow cytometry. We observed an increase of two- to six-fold in the number of epitopes recognised in the ubiquitin-fused fragments compared to the ubiquitin-fused full-length gag. In contrast, although proteasomal targeting was achieved, there was a marked reduction in the number of epitopes recognised in the ubiquitin-fused full-length gag compared to the full-length unmodified gene, but there were no differences in the number of epitope responses induced by non-ubiquitinated full-length gag and the ubiquitin-fused mini genes. Fragmentation and ubiquitination did not affect T cell memory differentiation and polyfunctionality, though most responses were directed against the Ad5 vector.Fragmentation but not fusion with ubiquitin increases the breadth of the CD8 T vaccine response against SIV-mac239 gag. Thus gene fragmentation of HIV vaccines may maximise responses.http://europepmc.org/articles/PMC3485275?pdf=render |
| spellingShingle | Adel Benlahrech Andrea Meiser Shanthi Herath Timos Papagatsias Takis Athanasopoulos Fucheng Li Steve Self Veronique Bachy Catherine Hervouet Karen Logan Linda Klavinskis George Dickson Steven Patterson Fragmentation of SIV-gag vaccine induces broader T cell responses. PLoS ONE |
| title | Fragmentation of SIV-gag vaccine induces broader T cell responses. |
| title_full | Fragmentation of SIV-gag vaccine induces broader T cell responses. |
| title_fullStr | Fragmentation of SIV-gag vaccine induces broader T cell responses. |
| title_full_unstemmed | Fragmentation of SIV-gag vaccine induces broader T cell responses. |
| title_short | Fragmentation of SIV-gag vaccine induces broader T cell responses. |
| title_sort | fragmentation of siv gag vaccine induces broader t cell responses |
| url | http://europepmc.org/articles/PMC3485275?pdf=render |
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