Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection.
The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinica...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005661&type=printable |
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| author | Matthias Hoffmann Nikos Pantazis Genevieve E Martin Stephen Hickling Jacob Hurst Jodi Meyerowitz Christian B Willberg Nicola Robinson Helen Brown Martin Fisher Sabine Kinloch Abdel Babiker Jonathan Weber Nneka Nwokolo Julie Fox Sarah Fidler Rodney Phillips John Frater SPARTAC and CHERUB Investigators |
| author_facet | Matthias Hoffmann Nikos Pantazis Genevieve E Martin Stephen Hickling Jacob Hurst Jodi Meyerowitz Christian B Willberg Nicola Robinson Helen Brown Martin Fisher Sabine Kinloch Abdel Babiker Jonathan Weber Nneka Nwokolo Julie Fox Sarah Fidler Rodney Phillips John Frater SPARTAC and CHERUB Investigators |
| author_sort | Matthias Hoffmann |
| collection | DOAJ |
| description | The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches. |
| format | Article |
| id | doaj-art-67fa8d272d054cf9b233919bf9cb97b9 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2016-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-67fa8d272d054cf9b233919bf9cb97b92025-08-20T02:03:19ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-07-01127e100566110.1371/journal.ppat.1005661Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection.Matthias HoffmannNikos PantazisGenevieve E MartinStephen HicklingJacob HurstJodi MeyerowitzChristian B WillbergNicola RobinsonHelen BrownMartin FisherSabine KinlochAbdel BabikerJonathan WeberNneka NwokoloJulie FoxSarah FidlerRodney PhillipsJohn FraterSPARTAC and CHERUB InvestigatorsThe rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005661&type=printable |
| spellingShingle | Matthias Hoffmann Nikos Pantazis Genevieve E Martin Stephen Hickling Jacob Hurst Jodi Meyerowitz Christian B Willberg Nicola Robinson Helen Brown Martin Fisher Sabine Kinloch Abdel Babiker Jonathan Weber Nneka Nwokolo Julie Fox Sarah Fidler Rodney Phillips John Frater SPARTAC and CHERUB Investigators Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. PLoS Pathogens |
| title | Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. |
| title_full | Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. |
| title_fullStr | Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. |
| title_full_unstemmed | Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. |
| title_short | Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. |
| title_sort | exhaustion of activated cd8 t cells predicts disease progression in primary hiv 1 infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005661&type=printable |
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