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oai:repisalud.isciii.es:20.500.12105/129752024-09-27T23:38:23Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609

00925njm 22002777a 4500 dc Planelles, V. author Szaniawski, M. author Williams, E. author Innis, E. author Martins, L. author Spivak, A. author Alcamí, José author Coiras, Mayte author 2019 Background: 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. J Virus Erad.2019;5 Supplement 3: 1-58. 2055-6640 http://hdl.handle.net/20.500.12105/12975 10.1016/S2055-6640(20)30075-3 Journal of Virus Eradication Tyrosine kinase inhibition: the new front in HIV cure efforts