Cargando…
IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation
The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the la...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484258/ https://www.ncbi.nlm.nih.gov/pubmed/36131914 http://dx.doi.org/10.3389/fimmu.2022.1001068 |
_version_ | 1784791843766009856 |
---|---|
author | Ezeonwumelu, Ifeanyi Jude García-Vidal, Edurne Felip, Eudald Puertas, Maria C. Oriol-Tordera, Bruna Gutiérrez-Chamorro, Lucía Gohr, André Ruiz-Riol, Marta Massanella, Marta Clotet, Bonaventura Martinez-Picado, Javier Badia, Roger Riveira-Muñoz, Eva Ballana, Ester |
author_facet | Ezeonwumelu, Ifeanyi Jude García-Vidal, Edurne Felip, Eudald Puertas, Maria C. Oriol-Tordera, Bruna Gutiérrez-Chamorro, Lucía Gohr, André Ruiz-Riol, Marta Massanella, Marta Clotet, Bonaventura Martinez-Picado, Javier Badia, Roger Riveira-Muñoz, Eva Ballana, Ester |
author_sort | Ezeonwumelu, Ifeanyi Jude |
collection | PubMed |
description | The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the latency reactivation capacity of a subclass of selective JAK2 inhibitors was characterized as a potential novel therapeutic strategy for HIV-1 cure. Notably, JAK2 inhibitors reversed HIV-1 latency in non-clonal lymphoid and myeloid in vitro models of HIV-1 latency and also ex vivo in CD4+ T cells from ART+ PWH, albeit its function was not dependent on JAK2 expression. Immunophenotypic characterization and whole transcriptomic profiling supported reactivation data, showing common gene expression signatures between latency reactivating agents (LRA; JAK2i fedratinib and PMA) in contrast to other JAK inhibitors, but with significantly fewer affected gene sets in the pathway analysis. In depth evaluation of differentially expressed genes, identified a significant upregulation of IRF7 expression despite the blockade of the JAK-STAT pathway and downregulation of proinflammatory cytokines and chemokines. Moreover, IRF7 expression levels positively correlated with HIV latency reactivation capacity of JAK2 inhibitors and also other common LRAs. Collectively, these results represent a promising step towards HIV eradication by demonstrating the potential of innate immune modulation for reducing the viral reservoir through a novel pathway driven by IRF7. |
format | Online Article Text |
id | pubmed-9484258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94842582022-09-20 IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation Ezeonwumelu, Ifeanyi Jude García-Vidal, Edurne Felip, Eudald Puertas, Maria C. Oriol-Tordera, Bruna Gutiérrez-Chamorro, Lucía Gohr, André Ruiz-Riol, Marta Massanella, Marta Clotet, Bonaventura Martinez-Picado, Javier Badia, Roger Riveira-Muñoz, Eva Ballana, Ester Front Immunol Immunology The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the latency reactivation capacity of a subclass of selective JAK2 inhibitors was characterized as a potential novel therapeutic strategy for HIV-1 cure. Notably, JAK2 inhibitors reversed HIV-1 latency in non-clonal lymphoid and myeloid in vitro models of HIV-1 latency and also ex vivo in CD4+ T cells from ART+ PWH, albeit its function was not dependent on JAK2 expression. Immunophenotypic characterization and whole transcriptomic profiling supported reactivation data, showing common gene expression signatures between latency reactivating agents (LRA; JAK2i fedratinib and PMA) in contrast to other JAK inhibitors, but with significantly fewer affected gene sets in the pathway analysis. In depth evaluation of differentially expressed genes, identified a significant upregulation of IRF7 expression despite the blockade of the JAK-STAT pathway and downregulation of proinflammatory cytokines and chemokines. Moreover, IRF7 expression levels positively correlated with HIV latency reactivation capacity of JAK2 inhibitors and also other common LRAs. Collectively, these results represent a promising step towards HIV eradication by demonstrating the potential of innate immune modulation for reducing the viral reservoir through a novel pathway driven by IRF7. Frontiers Media S.A. 2022-09-05 /pmc/articles/PMC9484258/ /pubmed/36131914 http://dx.doi.org/10.3389/fimmu.2022.1001068 Text en Copyright © 2022 Ezeonwumelu, García-Vidal, Felip, Puertas, Oriol-Tordera, Gutiérrez-Chamorro, Gohr, Ruiz-Riol, Massanella, Clotet, Martinez-Picado, Badia, Riveira-Muñoz and Ballana https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Ezeonwumelu, Ifeanyi Jude García-Vidal, Edurne Felip, Eudald Puertas, Maria C. Oriol-Tordera, Bruna Gutiérrez-Chamorro, Lucía Gohr, André Ruiz-Riol, Marta Massanella, Marta Clotet, Bonaventura Martinez-Picado, Javier Badia, Roger Riveira-Muñoz, Eva Ballana, Ester IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation |
title | IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation |
title_full | IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation |
title_fullStr | IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation |
title_full_unstemmed | IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation |
title_short | IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation |
title_sort | irf7 expression correlates with hiv latency reversal upon specific blockade of immune activation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484258/ https://www.ncbi.nlm.nih.gov/pubmed/36131914 http://dx.doi.org/10.3389/fimmu.2022.1001068 |
work_keys_str_mv | AT ezeonwumeluifeanyijude irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT garciavidaledurne irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT felipeudald irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT puertasmariac irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT orioltorderabruna irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT gutierrezchamorrolucia irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT gohrandre irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT ruizriolmarta irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT massanellamarta irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT clotetbonaventura irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT martinezpicadojavier irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT badiaroger irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT riveiramunozeva irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation AT ballanaester irf7expressioncorrelateswithhivlatencyreversaluponspecificblockadeofimmuneactivation |