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ResearchIn-Press PreviewAIDS/HIVImmunology Open Access | 10.1172/jci.insight.167329

The TLR7-IRF-5 axis sensitizes memory CD4+ T cells to Fas-mediated apoptosis during HIV-1 infection

Liseth Carmona-Perez,1 Xavier Dagenais-Lussier,1 Linh Thuy Mai,1 Tanja Stögerer,1 Sharada Swaminathan,1 Stephane Isnard,2 Matthew R. Rice,3 Betsy J. Barnes,4 Jean Pierre Routy,2 Julien van Grevenynghe,1 and Simona Stager5

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Carmona-Perez, L. in: JCI | PubMed | Google Scholar |

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Dagenais-Lussier, X. in: JCI | PubMed | Google Scholar

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Mai, L. in: JCI | PubMed | Google Scholar |

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Stögerer, T. in: JCI | PubMed | Google Scholar |

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Swaminathan, S. in: JCI | PubMed | Google Scholar

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Isnard, S. in: JCI | PubMed | Google Scholar

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Rice, M. in: JCI | PubMed | Google Scholar

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Barnes, B. in: JCI | PubMed | Google Scholar |

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Routy, J. in: JCI | PubMed | Google Scholar |

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by van Grevenynghe, J. in: JCI | PubMed | Google Scholar

1Immunology and Infectious Diseases, INRS - Centre Armand-Frappier, Laval, Canada

2Division of Hematology and Chronic Viral Illness Service, McGill University Health Centre Research Institute, Montréal, Canada

3Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, United States of America

4Feinstein Institutes for Medical Research, Manhasset, United States of America

5INRS - Centre Armand-Frappier, Laval, Canada

Find articles by Stager, S. in: JCI | PubMed | Google Scholar

Published May 25, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.167329.
Copyright © 2023, Carmona-Perez et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 25, 2023 - Version history
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Abstract

HIV-1 infection is characterized by a strong inflammatory environment, tissue disruption, and a progressive decline in CD4+ T cell count. Despite treatment with antiretroviral therapy (ART), the majority of persons living with HIV (PLWH) maintain residual levels of inflammation, low degree of immune activation, and higher sensitivity to cell death in their memory CD4+ T-cell compartment. To date, the mechanisms responsible for this high sensitivity remain elusive. We have identified the transcription factor IRF-5 to be involved in impairing the maintenance of murine CD4+ T cells in a chronic inflammatory environment. Here, we investigate whether IRF-5 also contributes to memory CD4+ T cell loss during HIV-1 infection.

We show that TLR7 and IRF-5 were upregulated in memory CD4+ T cells from PLWH, when compared with naturally protected elite controllers and HIVfree participants. TLR7 was upstream of IRF-5, promoting Caspase 8 expression in CD4+ T cells from ART HIV-1+ but not from HIVfree participants. Moreover, IRF-5 and TLR7 expression inversely correlated with CD4+ T cell counts in primary HIV infection. Interestingly, the TLR7-IRF-5 axis acted synergistically with the Fas/FasL pathway, suggesting that TLR7 and IRF-5 expression in ART HIV-1+ memory CD4+ T cells represents an imprint that predisposes cells to Fas-mediated apoptosis. This predisposition could be blocked using IRF-5 inhibitory peptides. Thus, we propose IRF-5 blockade as a possible therapy to prevent memory CD4+ T cell loss in PLWH.

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