HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice.
Viral diversity is considered a major impediment to the development of an effective HIV-1 vaccine. Despite this diversity, certain protein segments are nearly invariant across the known HIV-1 Group M sequences. We developed immunogens based on the highly conserved elements from the p24(gag) region a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3610668?pdf=render |
| _version_ | 1819198476067536896 |
|---|---|
| author | Viraj Kulkarni Margherita Rosati Antonio Valentin Brunda Ganneru Ashish K Singh Jian Yan Morgane Rolland Candido Alicea Rachel Kelly Beach Gen-Mu Zhang Sylvie Le Gall Kate E Broderick Niranjan Y Sardesai David Heckerman Beatriz Mothe Christian Brander David B Weiner James I Mullins George N Pavlakis Barbara K Felber |
| author_facet | Viraj Kulkarni Margherita Rosati Antonio Valentin Brunda Ganneru Ashish K Singh Jian Yan Morgane Rolland Candido Alicea Rachel Kelly Beach Gen-Mu Zhang Sylvie Le Gall Kate E Broderick Niranjan Y Sardesai David Heckerman Beatriz Mothe Christian Brander David B Weiner James I Mullins George N Pavlakis Barbara K Felber |
| author_sort | Viraj Kulkarni |
| collection | DOAJ |
| description | Viral diversity is considered a major impediment to the development of an effective HIV-1 vaccine. Despite this diversity, certain protein segments are nearly invariant across the known HIV-1 Group M sequences. We developed immunogens based on the highly conserved elements from the p24(gag) region according to two principles: the immunogen must (i) include strictly conserved elements of the virus that cannot mutate readily, and (ii) exclude both HIV regions capable of mutating without limiting virus viability, and also immunodominant epitopes located in variable regions. We engineered two HIV-1 p24(gag) DNA immunogens that express 7 highly Conserved Elements (CE) of 12-24 amino acids in length and differ by only 1 amino acid in each CE ('toggle site'), together covering >99% of the HIV-1 Group M sequences. Altering intracellular trafficking of the immunogens changed protein localization, stability, and also the nature of elicited immune responses. Immunization of C57BL/6 mice with p55(gag) DNA induced poor, CD4(+) mediated cellular responses, to only 2 of the 7 CE; in contrast, vaccination with p24CE DNA induced cross-clade reactive, robust T cell responses to 4 of the 7 CE. The responses were multifunctional and composed of both CD4(+) and CD8(+) T cells with mature cytotoxic phenotype. These findings provide a method to increase immune response to universally conserved Gag epitopes, using the p24CE immunogen. p24CE DNA vaccination induced humoral immune responses similar in magnitude to those induced by p55(gag), which recognize the virus encoded p24(gag) protein. The inclusion of DNA immunogens composed of conserved elements is a promising vaccine strategy to induce broader immunity by CD4(+) and CD8(+) T cells to additional regions of Gag compared to vaccination with p55(gag) DNA, achieving maximal cross-clade reactive cellular and humoral responses. |
| first_indexed | 2024-12-23T03:01:03Z |
| format | Article |
| id | doaj.art-6e5bcd65126b4ecd85d70afccbff0b95 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T03:01:03Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6e5bcd65126b4ecd85d70afccbff0b952022-12-21T18:02:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0183e6024510.1371/journal.pone.0060245HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice.Viraj KulkarniMargherita RosatiAntonio ValentinBrunda GanneruAshish K SinghJian YanMorgane RollandCandido AliceaRachel Kelly BeachGen-Mu ZhangSylvie Le GallKate E BroderickNiranjan Y SardesaiDavid HeckermanBeatriz MotheChristian BranderDavid B WeinerJames I MullinsGeorge N PavlakisBarbara K FelberViral diversity is considered a major impediment to the development of an effective HIV-1 vaccine. Despite this diversity, certain protein segments are nearly invariant across the known HIV-1 Group M sequences. We developed immunogens based on the highly conserved elements from the p24(gag) region according to two principles: the immunogen must (i) include strictly conserved elements of the virus that cannot mutate readily, and (ii) exclude both HIV regions capable of mutating without limiting virus viability, and also immunodominant epitopes located in variable regions. We engineered two HIV-1 p24(gag) DNA immunogens that express 7 highly Conserved Elements (CE) of 12-24 amino acids in length and differ by only 1 amino acid in each CE ('toggle site'), together covering >99% of the HIV-1 Group M sequences. Altering intracellular trafficking of the immunogens changed protein localization, stability, and also the nature of elicited immune responses. Immunization of C57BL/6 mice with p55(gag) DNA induced poor, CD4(+) mediated cellular responses, to only 2 of the 7 CE; in contrast, vaccination with p24CE DNA induced cross-clade reactive, robust T cell responses to 4 of the 7 CE. The responses were multifunctional and composed of both CD4(+) and CD8(+) T cells with mature cytotoxic phenotype. These findings provide a method to increase immune response to universally conserved Gag epitopes, using the p24CE immunogen. p24CE DNA vaccination induced humoral immune responses similar in magnitude to those induced by p55(gag), which recognize the virus encoded p24(gag) protein. The inclusion of DNA immunogens composed of conserved elements is a promising vaccine strategy to induce broader immunity by CD4(+) and CD8(+) T cells to additional regions of Gag compared to vaccination with p55(gag) DNA, achieving maximal cross-clade reactive cellular and humoral responses.http://europepmc.org/articles/PMC3610668?pdf=render |
| spellingShingle | Viraj Kulkarni Margherita Rosati Antonio Valentin Brunda Ganneru Ashish K Singh Jian Yan Morgane Rolland Candido Alicea Rachel Kelly Beach Gen-Mu Zhang Sylvie Le Gall Kate E Broderick Niranjan Y Sardesai David Heckerman Beatriz Mothe Christian Brander David B Weiner James I Mullins George N Pavlakis Barbara K Felber HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. PLoS ONE |
| title | HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. |
| title_full | HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. |
| title_fullStr | HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. |
| title_full_unstemmed | HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. |
| title_short | HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. |
| title_sort | hiv 1 p24 gag derived conserved element dna vaccine increases the breadth of immune response in mice |
| url | http://europepmc.org/articles/PMC3610668?pdf=render |
| work_keys_str_mv | AT virajkulkarni hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT margheritarosati hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT antoniovalentin hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT brundaganneru hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT ashishksingh hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT jianyan hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT morganerolland hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT candidoalicea hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT rachelkellybeach hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT genmuzhang hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT sylvielegall hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT kateebroderick hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT niranjanysardesai hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT davidheckerman hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT beatrizmothe hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT christianbrander hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT davidbweiner hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT jamesimullins hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT georgenpavlakis hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice AT barbarakfelber hiv1p24gagderivedconservedelementdnavaccineincreasesthebreadthofimmuneresponseinmice |