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referenced object 'lBB48' cannot be found Offset: 3188621 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'lBB49' cannot be found Offset: 3188621 MIMEtype: application/pdf PDFMetadata: Objects: 609 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: false CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: RESULTS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Children: Item: Title: Sirtuin-2, a novel plasma biomarker in HIV infection. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Time to cART initiation is associated with plasma SIRT2 levels and neurological dysfunction. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: In vitro SIRT2 targeting reduces HIV replication and virus reactivation. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: DISCUSSION Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: MATERIALS AND METHODS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Children: Item: Title: Patients. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: Proteomic analysis. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Proximity extension assay. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Ultrasensitive single-molecule array. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: SIRT2 enzyme-linked immunosorbent assay. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: Neuropsychological assessment. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Item: Title: Brain image assessment. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Item: Title: Bioinformatic analysis of published transcriptomics. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: Real-time PCR. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: Determination of HIV proviral DNA. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Item: Title: HIV replication of PHA blasts and monocyte-derived macrophages. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4a87761d Item: Title: HIV replication of microglial cells. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89 Item: Title: In vitro HIV reactivation. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9 Item: Title: Statistical analysis. Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e Item: Title: SUPPLEMENTAL MATERIAL Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4671e53b Item: Title: ACKNOWLEDGMENTS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@2db7a79b Item: Title: REFERENCES Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6950e31 Info: Title: Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction Author: Clara Duran-Castells;Anuska Llano;Ai Kawana-Tachikawa;Anna Prats;Ignacio Martinez-Zalacain;Mie Kobayashi-Ishihara;Bruna Oriol-Tordera;Ruth Peña;Cristina Gálvez;Sandra Silva-Arrieta;Bonaventura Clotet;Eva Riveira-Muñoz;Esther Ballana;Julia G. Prado;Javier Martinez-Picado;Jorge Sanchez;Beatriz Mothe;Dennis Hartigan-O’Connor;Tony Wyss-Coray;Andreas Meyerhans;Magnus Gisslén;Richard W. Price;Carles Soriano-Mas;José Antonio Muñoz-Moreno;Christian Brander;Marta Ruiz-Riol Subject: Virus-Cell Interactions Keywords: HIV-1; virus infection control; neurological disorder; plasma proteomics; HIV reservoir; neuroimaging; HIV-associated neurocognitive disorders (HAND) Creator: PTC Arbortext Advanced Print Publisher 11.1.4012/W Producer: Adobe LiveCycle PDF Generator; modified using iText® 5.5.13.2 ©2000-2020 iText Group NV (AGPL-version) CreationDate: Sat Feb 11 08:43:08 CET 2023 ModDate: Mon Feb 13 18:33:05 CET 2023 ID: 0x7708ef40cdbf8bcaf33e2273a1083521, 0x89028347ade1db8fd83483fd5cc558c3 Filters: FilterPipeline: FlateDecode Images: Image: NisoImageMetadata: FormatName: image/png ImageWidth: 67 ImageHeight: 67 BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Fonts: Type1: Font: BaseFont: EEHAAG+AdvP4C4E74 FontSubset: true FirstChar: 1 LastChar: 3 FontDescriptor: FontName: EEHAAG+AdvP4C4E74 Flags: Symbolic FontBBox: -20, -958, 1114, 770 FontFile3: true 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-20, -208, 1000, 770 FontFile3: true Encoding: WinAnsiEncoding XMP: Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction 10.1128/jvi.01655-22 Clara Duran-Castells Anuska Llano Ai Kawana-Tachikawa Anna Prats Ignacio Martinez-Zalacain Mie Kobayashi-Ishihara Bruna Oriol-Tordera Ruth Peña Cristina Gálvez Sandra Silva-Arrieta Bonaventura Clotet Eva Riveira-Muñoz Esther Ballana Julia G. Prado Javier Martinez-Picado Jorge Sanchez Beatriz Mothe Dennis Hartigan-O’Connor Tony Wyss-Coray Andreas Meyerhans Magnus Gisslén Richard W. Price Carles Soriano-Mas José Antonio Muñoz-Moreno Christian Brander Marta Ruiz-Riol Virus-Cell Interactions Virus-Cell Interactions HIV-1 virus infection control neurological disorder plasma proteomics HIV reservoir neuroimaging HIV-associated neurocognitive disorders (HAND) American Society for Microbiology Duran-Castells et al. Copyright © 2023 Duran-Castells et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. 20230131 2023 ABSTRACT The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction. 20221025 20221220 1098-5514 Pages: Page: Label: 1 Annotations: Annotation: Subtype: Link Rect: 200, 565, 284, 574 Annotation: Subtype: Link Rect: 50, 543, 105, 552 Annotation: Subtype: Link Rect: 186, 543, 274, 552 Annotation: Subtype: Link Rect: 363, 543, 417, 552 Annotation: Subtype: Link Rect: 264, 520, 324, 529 Annotation: Subtype: Link Rect: 435, 124, 530, 131 Annotation: Subtype: Link Rect: 400, 115, 456, 122 Annotation: Subtype: Link Rect: 465, 24, 526, 31 Annotation: Subtype: Link Rect: 508, 683, 544, 719 Page: Label: 2 Annotations: Annotation: Subtype: Link Rect: 330, 422, 334, 431 Destination: 264 Annotation: Subtype: Link Rect: 67, 385, 72, 394 Destination: 264 Annotation: Subtype: Link Rect: 83, 373, 88, 382 Destination: null Annotation: Subtype: Link Rect: 241, 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