Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction
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 f...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:272871 |
| Acceso en línea: | https://ddd.uab.cat/record/272871 https://dx.doi.org/urn:doi:10.1128/jvi.01655-22 |
| Access Level: | acceso abierto |
| Palabra clave: | HIV-1 Virus infection control Neurological disorder Plasma proteomics HIV reservoir Neuroimaging HIV-associated neurocognitive disorders (HAND) |
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oai:ddd.uab.cat:272871 |
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España |
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| dc.title.none.fl_str_mv |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| title |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| spellingShingle |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction Duran-Castells, Clara|||0000-0002-4034-5738 HIV-1 Virus infection control Neurological disorder Plasma proteomics HIV reservoir Neuroimaging HIV-associated neurocognitive disorders (HAND) |
| title_short |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| title_full |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| title_fullStr |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| title_full_unstemmed |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| title_sort |
Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction |
| dc.creator.none.fl_str_mv |
Duran-Castells, Clara|||0000-0002-4034-5738 Llano Montero, Anuska|||0000-0002-0133-9888 Kawana-Tachikawa, Ai|||0000-0002-3082-5324 Prats, Anna|||0000-0002-3586-4525 Martinez-Zalacain, Ignacio Kobayashi-Ishihara, Mie|||0000-0001-6342-9451 Oriol-Tordera, Bruna|||0000-0002-2714-9097 Peña, Ruth Gálvez, Cristina|||0000-0002-2286-6193 Silva-Arrieta, Sandra Clotet Sala, Bonaventura|||0000-0003-3232-4598 Riveira Muñoz, Eva|||0000-0002-6396-1162 Ballana, Ester|||0000-0002-5215-7363 Prado, Julia G.|||0000-0002-5439-4645 Martínez Picado, Francisco Javier|||0000-0002-4916-2129 Sanchez, Jorge Mothe, Beatriz|||0000-0001-9975-407X Hartigan-O'Connor, Dennis Wyss-Coray, Tony Meyerhans, Andreas|||0000-0003-0620-5317 Gisslén, Magnus Price, Richard W. Soriano-Mas, Carles|||0000-0003-4574-6597 Muñoz-Moreno, José Antonio|||0000-0002-7239-5422 Brander, Christian|||0000-0002-0548-5778 Ruiz Riol, Marta|||0000-0003-1899-8879 |
| author |
Duran-Castells, Clara|||0000-0002-4034-5738 |
| author_facet |
Duran-Castells, Clara|||0000-0002-4034-5738 Llano Montero, Anuska|||0000-0002-0133-9888 Kawana-Tachikawa, Ai|||0000-0002-3082-5324 Prats, Anna|||0000-0002-3586-4525 Martinez-Zalacain, Ignacio Kobayashi-Ishihara, Mie|||0000-0001-6342-9451 Oriol-Tordera, Bruna|||0000-0002-2714-9097 Peña, Ruth Gálvez, Cristina|||0000-0002-2286-6193 Silva-Arrieta, Sandra Clotet Sala, Bonaventura|||0000-0003-3232-4598 Riveira Muñoz, Eva|||0000-0002-6396-1162 Ballana, Ester|||0000-0002-5215-7363 Prado, Julia G.|||0000-0002-5439-4645 Martínez Picado, Francisco Javier|||0000-0002-4916-2129 Sanchez, Jorge Mothe, Beatriz|||0000-0001-9975-407X Hartigan-O'Connor, Dennis Wyss-Coray, Tony Meyerhans, Andreas|||0000-0003-0620-5317 Gisslén, Magnus Price, Richard W. Soriano-Mas, Carles|||0000-0003-4574-6597 Muñoz-Moreno, José Antonio|||0000-0002-7239-5422 Brander, Christian|||0000-0002-0548-5778 Ruiz Riol, Marta|||0000-0003-1899-8879 |
| author_role |
author |
| author2 |
Llano Montero, Anuska|||0000-0002-0133-9888 Kawana-Tachikawa, Ai|||0000-0002-3082-5324 Prats, Anna|||0000-0002-3586-4525 Martinez-Zalacain, Ignacio Kobayashi-Ishihara, Mie|||0000-0001-6342-9451 Oriol-Tordera, Bruna|||0000-0002-2714-9097 Peña, Ruth Gálvez, Cristina|||0000-0002-2286-6193 Silva-Arrieta, Sandra Clotet Sala, Bonaventura|||0000-0003-3232-4598 Riveira Muñoz, Eva|||0000-0002-6396-1162 Ballana, Ester|||0000-0002-5215-7363 Prado, Julia G.|||0000-0002-5439-4645 Martínez Picado, Francisco Javier|||0000-0002-4916-2129 Sanchez, Jorge Mothe, Beatriz|||0000-0001-9975-407X Hartigan-O'Connor, Dennis Wyss-Coray, Tony Meyerhans, Andreas|||0000-0003-0620-5317 Gisslén, Magnus Price, Richard W. Soriano-Mas, Carles|||0000-0003-4574-6597 Muñoz-Moreno, José Antonio|||0000-0002-7239-5422 Brander, Christian|||0000-0002-0548-5778 Ruiz Riol, Marta|||0000-0003-1899-8879 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
HIV-1 Virus infection control Neurological disorder Plasma proteomics HIV reservoir Neuroimaging HIV-associated neurocognitive disorders (HAND) |
| topic |
HIV-1 Virus infection control Neurological disorder Plasma proteomics HIV reservoir Neuroimaging HIV-associated neurocognitive disorders (HAND) |
| description |
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. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2 2023-01-01 2023 2023-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/272871 https://dx.doi.org/urn:doi:10.1128/jvi.01655-22 |
| url |
https://ddd.uab.cat/record/272871 https://dx.doi.org/urn:doi:10.1128/jvi.01655-22 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
European Commission https://doi.org/10.13039/501100000780 681137 Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2012-32078 Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-119710RB-I00 Ministerio de Educación, Cultura y Deporte https://doi.org/10.13039/501100003176 FPU15/03698 Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 FI17/00294 Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CPII19/00012 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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Universitat Autònoma de Barcelona |
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Dipòsit Digital de Documents de la UAB |
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1869407600291872768 |
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Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological DysfunctionDuran-Castells, Clara|||0000-0002-4034-5738Llano Montero, Anuska|||0000-0002-0133-9888Kawana-Tachikawa, Ai|||0000-0002-3082-5324Prats, Anna|||0000-0002-3586-4525Martinez-Zalacain, IgnacioKobayashi-Ishihara, Mie|||0000-0001-6342-9451Oriol-Tordera, Bruna|||0000-0002-2714-9097Peña, RuthGálvez, Cristina|||0000-0002-2286-6193Silva-Arrieta, SandraClotet Sala, Bonaventura|||0000-0003-3232-4598Riveira Muñoz, Eva|||0000-0002-6396-1162Ballana, Ester|||0000-0002-5215-7363Prado, Julia G.|||0000-0002-5439-4645Martínez Picado, Francisco Javier|||0000-0002-4916-2129Sanchez, JorgeMothe, Beatriz|||0000-0001-9975-407XHartigan-O'Connor, DennisWyss-Coray, TonyMeyerhans, Andreas|||0000-0003-0620-5317Gisslén, MagnusPrice, Richard W.Soriano-Mas, Carles|||0000-0003-4574-6597Muñoz-Moreno, José Antonio|||0000-0002-7239-5422Brander, Christian|||0000-0002-0548-5778Ruiz Riol, Marta|||0000-0003-1899-8879HIV-1Virus infection controlNeurological disorderPlasma proteomicsHIV reservoirNeuroimagingHIV-associated neurocognitive disorders (HAND)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. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/272871https://dx.doi.org/urn:doi:10.1128/jvi.01655-22reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengEuropean Commission https://doi.org/10.13039/501100000780 681137Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2012-32078Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-119710RB-I00Ministerio de Educación, Cultura y Deporte https://doi.org/10.13039/501100003176 FPU15/03698Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 FI17/00294Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CPII19/00012open accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2728712026-06-06T12:50:31Z |
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15.301629 |