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CD8 T cell response maturation defined by anentropic specificity and repertoire depth correlates with SIVΔnef-induced protection.

Adnan S, Colantonio AD, Yu Y, Gillis J, Wong FE, Becker EA, Piatak M, Reeves RK, Lifson JD, O'Connor SL, Johnson RP - PLoS Pathog. (2015)

Bottom Line: Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period.These results correlate SIVΔnef-induced protection with expanded anentropic specificity and increased response depth.Importantly, these findings render SIVΔnef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design.

View Article: PubMed Central - PubMed

Affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.

ABSTRACT
The live attenuated simian immunodeficiency virus (LASIV) vaccine SIVΔnef is one of the most effective vaccines in inducing protection against wild-type lentiviral challenge, yet little is known about the mechanisms underlying its remarkable protective efficacy. Here, we exploit deep sequencing technology and comprehensive CD8 T cell epitope mapping to deconstruct the CD8 T cell response, to identify the regions of immune pressure and viral escape, and to delineate the effect of epitope escape on the evolution of the CD8 T cell response in SIVΔnef-vaccinated animals. We demonstrate that the initial CD8 T cell response in the acute phase of SIVΔnef infection is mounted predominantly against more variable epitopes, followed by widespread sequence evolution and viral escape. Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period. These results correlate SIVΔnef-induced protection with expanded anentropic specificity and increased response depth. Importantly, these findings render SIVΔnef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design.

No MeSH data available.


Related in: MedlinePlus

As entropic epitopes escape, the CD8 T cell responses specific for these epitopes wane.(A) The four immunodominant epitopes from all animals were plotted according to their entropies and whether they escaped the CD8 T cell response. Anentropic epitopes demonstrated significantly less escape than highly entropic epitopes. Anentropic epitopes were predominantly from Gag and Pol. (B) While CD8 T cell responses targeting conserved epitopes were maintained over time, responses specific to variable epitopes declined in magnitude.
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ppat.1004633.g006: As entropic epitopes escape, the CD8 T cell responses specific for these epitopes wane.(A) The four immunodominant epitopes from all animals were plotted according to their entropies and whether they escaped the CD8 T cell response. Anentropic epitopes demonstrated significantly less escape than highly entropic epitopes. Anentropic epitopes were predominantly from Gag and Pol. (B) While CD8 T cell responses targeting conserved epitopes were maintained over time, responses specific to variable epitopes declined in magnitude.

Mentions: However, we did not observe sequence variation in all identified CD8 T cell epitopes. As expected, we observed a strong bias favoring the escape of responses targeting highly variable epitopes, as determined by calculated entropy scores. An analysis of the top four responses mapped for each animal at weeks 5, 20 and 40 after SIVΔnef vaccination demonstrated that the escaped epitopes had significantly higher entropy scores than targeted epitopes that did not escape (p = 0.0013) (Fig. 6A). Similarly, SIV-specific CD8 T cells can be grouped into maintained responses, which target mostly conserved regions, and waning responses that target escaped epitopes. The magnitude of the variable responses, defined as targeting epitopes with an entropy above 0.25, decreased significantly between weeks 5 and 20 (p = .0101) and between weeks 5 and 40 (p = .0449), whereas the magnitude of the conserved responses was maintained (Fig. 6B).


CD8 T cell response maturation defined by anentropic specificity and repertoire depth correlates with SIVΔnef-induced protection.

Adnan S, Colantonio AD, Yu Y, Gillis J, Wong FE, Becker EA, Piatak M, Reeves RK, Lifson JD, O'Connor SL, Johnson RP - PLoS Pathog. (2015)

As entropic epitopes escape, the CD8 T cell responses specific for these epitopes wane.(A) The four immunodominant epitopes from all animals were plotted according to their entropies and whether they escaped the CD8 T cell response. Anentropic epitopes demonstrated significantly less escape than highly entropic epitopes. Anentropic epitopes were predominantly from Gag and Pol. (B) While CD8 T cell responses targeting conserved epitopes were maintained over time, responses specific to variable epitopes declined in magnitude.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334552&req=5

ppat.1004633.g006: As entropic epitopes escape, the CD8 T cell responses specific for these epitopes wane.(A) The four immunodominant epitopes from all animals were plotted according to their entropies and whether they escaped the CD8 T cell response. Anentropic epitopes demonstrated significantly less escape than highly entropic epitopes. Anentropic epitopes were predominantly from Gag and Pol. (B) While CD8 T cell responses targeting conserved epitopes were maintained over time, responses specific to variable epitopes declined in magnitude.
Mentions: However, we did not observe sequence variation in all identified CD8 T cell epitopes. As expected, we observed a strong bias favoring the escape of responses targeting highly variable epitopes, as determined by calculated entropy scores. An analysis of the top four responses mapped for each animal at weeks 5, 20 and 40 after SIVΔnef vaccination demonstrated that the escaped epitopes had significantly higher entropy scores than targeted epitopes that did not escape (p = 0.0013) (Fig. 6A). Similarly, SIV-specific CD8 T cells can be grouped into maintained responses, which target mostly conserved regions, and waning responses that target escaped epitopes. The magnitude of the variable responses, defined as targeting epitopes with an entropy above 0.25, decreased significantly between weeks 5 and 20 (p = .0101) and between weeks 5 and 40 (p = .0449), whereas the magnitude of the conserved responses was maintained (Fig. 6B).

Bottom Line: Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period.These results correlate SIVΔnef-induced protection with expanded anentropic specificity and increased response depth.Importantly, these findings render SIVΔnef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design.

View Article: PubMed Central - PubMed

Affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.

ABSTRACT
The live attenuated simian immunodeficiency virus (LASIV) vaccine SIVΔnef is one of the most effective vaccines in inducing protection against wild-type lentiviral challenge, yet little is known about the mechanisms underlying its remarkable protective efficacy. Here, we exploit deep sequencing technology and comprehensive CD8 T cell epitope mapping to deconstruct the CD8 T cell response, to identify the regions of immune pressure and viral escape, and to delineate the effect of epitope escape on the evolution of the CD8 T cell response in SIVΔnef-vaccinated animals. We demonstrate that the initial CD8 T cell response in the acute phase of SIVΔnef infection is mounted predominantly against more variable epitopes, followed by widespread sequence evolution and viral escape. Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period. These results correlate SIVΔnef-induced protection with expanded anentropic specificity and increased response depth. Importantly, these findings render SIVΔnef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design.

No MeSH data available.


Related in: MedlinePlus