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| Home > Articles > Published articles > Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection |
| Home > Articles > Published articles > Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection |
(Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Universitat Autònoma de Barcelona. Departament de Medicina) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)| Date: | 2022 |
| Abstract: | 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. |
| Grants: | Instituto de Salud Carlos III PI19/00194 "la Caixa" Foundation LCF/BQ/IN18/11660017 European Commission. Horizon 2020 713673 Agència de Gestió d'Ajuts Universitaris i de Recerca 2019 FI-B00420 Instituto de Salud Carlos III FIS/CM20/00027 Instituto de Salud Carlos III FIS/CP19/00011 Instituto de Salud Carlos III FIS/CPII19/00012 Ministerio de Ciencia e Innovación RYC2020-028934-I |
| 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 ; Latency reversing agents ; IKK ; TANK binding kinase-1 |
| Published in: | International journal of molecular sciences, Vol. 23 Núm. 23 (november 2022) , p. 15000, ISSN 1422-0067 |
