| Autor: |
Ezeonwumelu IJ; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain., Garcia-Vidal E; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain., Riveira-Muñoz E; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain., Felip E; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain.; Health Research Institute Germans Trias i Pujol (IGTP), Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.; Medical Oncology Department, Catalan Institute of Oncology, Badalona-Applied Research Group in Oncology (B-ARGO), 08916 Badalona, Spain., Gutiérrez-Chamorro L; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain., Calba I; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain.; Health Research Institute Germans Trias i Pujol (IGTP), Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain., Massanella M; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain.; University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain., Sirera G; Fight Infections Foundation, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain., Clotet B; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain.; University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain., Ballana E; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain.; Health Research Institute Germans Trias i Pujol (IGTP), Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain., Badia R; IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Can Ruti Campus, 08916 Badalona, Spain.; Health Research Institute Germans Trias i Pujol (IGTP), Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. |
| Abstrakt: |
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. |
