41a84d91f35860c2d15e4d337f04edde ijms-23-15000.pdf dff52714cbf066e7fa978656c4ac40146b19c650 ijms-23-15000.pdf 17c7f2bce42725bc96046e0d3bc2eb9d75e97d66040a517b43b1bc5f9c81062a ijms-23-15000.pdf Title: Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection Subject: 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-B (IB) 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 IKK (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. Keywords: HIV-1; latency reversing agents; IKK; TANK binding kinase-1 Author: Ifeanyi Jude Ezeonwumelu, Edurne Garcia-Vidal, Eva Riveira-Muñoz, Eudald Felip, Lucía Gutiérrez-Chamorro, Ignasi Calba, Marta Massanella, Guillem Sirera, Bonaventura Clotet, Ester Ballana and Roger Badia Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Nov 30 08:04:16 2022 CET ModDate: Wed Nov 30 08:28:56 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1628225 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YSPQJI+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 DDMOHK+VnURWPalladioL Type 1 Custom yes yes no 15 0 IRRKTU+EURM10 Type 1 Builtin yes yes no 19 0 NLRXZK+URWPalladioL-Bold Type 1 Custom yes yes no 23 0 AWEPIO+URWPalladioL-Roma Type 1 Custom 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IPFAPG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 154 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-24 02:38:25 CEST RepresentationInformation: ijms-23-15000.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-06-23 15:07:43 CEST Size: 1628225 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 336 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: IKKis Induce HIV Reactivation in Distinct Models of HIV Latency In Vitro Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: TBK1/IKK and IKK Inhibitors Induce HIV Reactivation Ex Vivo in CD4+ T Cells from HIV+ Individuals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Antiretroviral Drugs Do Not Interfere with HIV Reactivation Activity Induced by IKKis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: IKKis Do Not Modify Cell Activation in Ex Vivo Treated Primary CD4+ T Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Compounds Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Virus Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Generation of Latently Infected Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: HIV Reactivation In Vitro in Latently Infected Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Measurement of HIV Production in CD4+ T Cells from HIV+ Individuals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Quantitative RT-Polymerase Chain Reaction (qRT-PCR) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Western Blot Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Flow Cytometry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Evaluation of Cytotoxicity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Anti-HIV Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Statistical Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Info: Title: Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection Author: Ifeanyi Jude Ezeonwumelu, Edurne Garcia-Vidal, Eva Riveira-Muñoz, Eudald Felip, Lucía Gutiérrez-Chamorro, Ignasi Calba, Marta Massanella, Guillem Sirera, Bonaventura Clotet, Ester Ballana and Roger Badia Subject: 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-B (IB) 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 IKK (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. 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