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dc.contributor.authorPlanelles, V.
dc.contributor.authorSzaniawski, M.
dc.contributor.authorWilliams, E.
dc.contributor.authorInnis, E.
dc.contributor.authorMartins, L.
dc.contributor.authorSpivak, A.
dc.contributor.authorAlcamí, José 
dc.contributor.authorCoiras, Mayte 
dc.date.accessioned2021-05-18T07:38:35Z
dc.date.available2021-05-18T07:38:35Z
dc.date.issued2019
dc.identifier.citationJ Virus Erad.2019;5 Supplement 3: 1-58.es_ES
dc.identifier.issn2055-6640es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/12975
dc.descriptionMonográfico con los resúmenes del Ninth International Workshop on HIV Persistence during Therapy 10-13 December 2019, Miami, Florida, USAes_ES
dc.description.abstractBackground: The HIV-1 latent reservoir persists largely through the natural ability of memory T cells to homeostatically proliferate in response to gc-cytokines IL-7 and IL-15. In addition, HIV-1 also infects cells of the myeloid lineage, a cell type that can penetrate protected tissues including the central nervous system. Dasatinib and related tyrosine kinase inhibitors (TKI) that are FDA-approved for the treatment of chronic myeloid leukemia have several novel activities that can impact HIV-1 infection and the persistence of latent reservoirs. The first activity of dasatinib is the ability to block homeostatic proliferation. A second activity of dasatinib is its ability to block infection by HIV-1 by an unusual mechanism that involves dephosphorylation and activation of SAMHD1, a potent viral restriction factor. Methods: To investigate the ability of TKIs to inhibit homeostatic proliferation of CD4+ T lymphocytes, we utilized a previously described model of latency based on primary cells, and induced proliferation via incubation with IL-2, IL-7 and IL-15. To study the inhibition of phosphorylation of SAMHD1, we cultured primary monocyte derived macrophages and incubated them with TKI for 24hrs and then exposed them to HIV-1 Bal. SAMHD1 phosphorylation was evaluated by Western blot and flow cytometry. Results: We demonstrate that TKIs block the homeostatic prolif eration of latently infected T cells and thus prevent maintenance of the latent reservoir, and predict that this will result in accelerated decay over time. In vitro measurements demonstrate that various TKIs exhibit highly different inhibitory potency on lymphocyte proliferation. We also observed that TKIs phenocopied the documented effects of types I and II IFNs on SAMHD1 dephosphorylation. The signaling pathway downstream of TKI is not associated with modulation of cyclin dependent kinases and is, therefore, different from that following IFN signalling. The relative potencies of TKI (dasatinib, ponatinib, palbociclic, imatinib) in inhibiting cell proliferation did not correlate with the potencies at inhibiting phosphorylation of SAMHD1. Therefore, we speculate that the tyrosine kinase targets for both activities are likely different. Conclusions: We conclude that TKI in vitro exhibit two different antiviral activities that are specific for HIV-1 and propose further development of these potentially exciting therapeutics.
dc.language.isoenges_ES
dc.publisherElsevier es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleTyrosine kinase inhibition: the new front in HIV cure effortses_ES
dc.typeconference posteres_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.format.volume5es_ES
dc.format.numbersuples_ES
dc.format.page3es_ES
dc.identifier.doi10.1016/S2055-6640(20)30075-3es_ES
dc.description.peerreviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.1016/S2055-6640(20)30075-3es_ES
dc.identifier.journalJournal of Virus Eradicationes_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.repisalud.institucionISCIIIes_ES
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 Internacional