Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses.
Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus contro...
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doaj-ce5e0a43cdad46a7a2a68077695ec7392020-11-24T22:10:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-02-01112e100465810.1371/journal.ppat.1004658Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses.Gemma HancockHongbing YangElisabeth YorkeEmma WainwrightVictoria BourneAlyse FrisbeeTamika L PayneMark BerrongGuido FerrariDenis ChoperaTomas HankeBeatriz MotheChristian BranderM Juliana McElrathAndrew McMichaelNilu GoonetillekeGeorgia D TomarasNicole FrahmLucy DorrellDefining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.http://europepmc.org/articles/PMC4344337?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gemma Hancock Hongbing Yang Elisabeth Yorke Emma Wainwright Victoria Bourne Alyse Frisbee Tamika L Payne Mark Berrong Guido Ferrari Denis Chopera Tomas Hanke Beatriz Mothe Christian Brander M Juliana McElrath Andrew McMichael Nilu Goonetilleke Georgia D Tomaras Nicole Frahm Lucy Dorrell |
spellingShingle |
Gemma Hancock Hongbing Yang Elisabeth Yorke Emma Wainwright Victoria Bourne Alyse Frisbee Tamika L Payne Mark Berrong Guido Ferrari Denis Chopera Tomas Hanke Beatriz Mothe Christian Brander M Juliana McElrath Andrew McMichael Nilu Goonetilleke Georgia D Tomaras Nicole Frahm Lucy Dorrell Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. PLoS Pathogens |
author_facet |
Gemma Hancock Hongbing Yang Elisabeth Yorke Emma Wainwright Victoria Bourne Alyse Frisbee Tamika L Payne Mark Berrong Guido Ferrari Denis Chopera Tomas Hanke Beatriz Mothe Christian Brander M Juliana McElrath Andrew McMichael Nilu Goonetilleke Georgia D Tomaras Nicole Frahm Lucy Dorrell |
author_sort |
Gemma Hancock |
title |
Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. |
title_short |
Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. |
title_full |
Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. |
title_fullStr |
Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. |
title_full_unstemmed |
Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. |
title_sort |
identification of effective subdominant anti-hiv-1 cd8+ t cells within entire post-infection and post-vaccination immune responses. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2015-02-01 |
description |
Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control. |
url |
http://europepmc.org/articles/PMC4344337?pdf=render |
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