IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation
Ezeonwumelu, I.J (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
García Vidal, Edurne (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Felip, Eudald (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Puertas, Maria C. (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Oriol-Tordera, Bruna (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Gutiérrez-Chamorro, Lucía (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Gohr, André (Max Planck Institute of Molecular Cell Biology and Genetics)
Ruiz Riol, Marta (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Massanella, Marta (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Martínez Picado, Francisco Javier (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Badia, Roger (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Riveira-Muñoz, Eva (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Ballana, Ester (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	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.
Grants:	Instituto de Salud Carlos III PI19/00194 Agencia Estatal de Investigación PID2019-109870RB-I00
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	HIV-1 cure strategies ; Innate immunity ; IRF7 ; JAK-STAT signalling ; Latency reversal agents
Published in:	Frontiers in immunology, Vol. 13 (september 2022) , ISSN 1664-3224

DOI: 10.3389/fimmu.2022.1001068
PMID: 36131914

18 p, 6.6 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles