Cargando…

Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection

HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kina...

Descripción completa

Detalles Bibliográficos
Autores principales: Ezeonwumelu, Ifeanyi Jude, Garcia-Vidal, Edurne, Riveira-Muñoz, Eva, Felip, Eudald, Gutiérrez-Chamorro, Lucía, Calba, Ignasi, Massanella, Marta, Sirera, Guillem, Clotet, Bonaventura, Ballana, Ester, Badia, Roger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741028/
https://www.ncbi.nlm.nih.gov/pubmed/36499329
http://dx.doi.org/10.3390/ijms232315000
_version_ 1784848215178215424
author Ezeonwumelu, Ifeanyi Jude
Garcia-Vidal, Edurne
Riveira-Muñoz, Eva
Felip, Eudald
Gutiérrez-Chamorro, Lucía
Calba, Ignasi
Massanella, Marta
Sirera, Guillem
Clotet, Bonaventura
Ballana, Ester
Badia, Roger
author_facet Ezeonwumelu, Ifeanyi Jude
Garcia-Vidal, Edurne
Riveira-Muñoz, Eva
Felip, Eudald
Gutiérrez-Chamorro, Lucía
Calba, Ignasi
Massanella, Marta
Sirera, Guillem
Clotet, Bonaventura
Ballana, Ester
Badia, Roger
author_sort Ezeonwumelu, Ifeanyi Jude
collection PubMed
description HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kinases (TBK1) as a novel pathway to reverse HIV-1 latency in latently infected non-clonal lymphoid and myeloid cell in vitro models. IKK inhibitors (IKKis) triggered up to a 1.8-fold increase in HIV reactivation in both, myeloid and lymphoid cell models. The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKβ (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo. More importantly, although none of the compounds tested showed antiviral activity, the combination of the distinct IKKis with ART did not affect the latency reactivation nor blockade of HIV infection by ART. Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection.
format Online
Article
Text
id pubmed-9741028
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97410282022-12-11 Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection Ezeonwumelu, Ifeanyi Jude Garcia-Vidal, Edurne Riveira-Muñoz, Eva Felip, Eudald Gutiérrez-Chamorro, Lucía Calba, Ignasi Massanella, Marta Sirera, Guillem Clotet, Bonaventura Ballana, Ester Badia, Roger Int J Mol Sci Brief Report HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kinases (TBK1) as a novel pathway to reverse HIV-1 latency in latently infected non-clonal lymphoid and myeloid cell in vitro models. IKK inhibitors (IKKis) triggered up to a 1.8-fold increase in HIV reactivation in both, myeloid and lymphoid cell models. The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKβ (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo. More importantly, although none of the compounds tested showed antiviral activity, the combination of the distinct IKKis with ART did not affect the latency reactivation nor blockade of HIV infection by ART. Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection. MDPI 2022-11-30 /pmc/articles/PMC9741028/ /pubmed/36499329 http://dx.doi.org/10.3390/ijms232315000 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Ezeonwumelu, Ifeanyi Jude
Garcia-Vidal, Edurne
Riveira-Muñoz, Eva
Felip, Eudald
Gutiérrez-Chamorro, Lucía
Calba, Ignasi
Massanella, Marta
Sirera, Guillem
Clotet, Bonaventura
Ballana, Ester
Badia, Roger
Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection
title Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection
title_full Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection
title_fullStr Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection
title_full_unstemmed Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection
title_short Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection
title_sort pharmacological inhibition of ikk to tackle latency and hyperinflammation in chronic hiv-1 infection
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741028/
https://www.ncbi.nlm.nih.gov/pubmed/36499329
http://dx.doi.org/10.3390/ijms232315000
work_keys_str_mv AT ezeonwumeluifeanyijude pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT garciavidaledurne pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT riveiramunozeva pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT felipeudald pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT gutierrezchamorrolucia pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT calbaignasi pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT massanellamarta pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT sireraguillem pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT clotetbonaventura pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT ballanaester pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection
AT badiaroger pharmacologicalinhibitionofikktotacklelatencyandhyperinflammationinchronichiv1infection