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00925njm 22002777a 4500 dc Rodriguez Mora, Sara author Sánchez-Menéndez, Clara author Bautista-Carrascosa, Guiomar author Mateos, Elena author Moreno-Serna, Lucia author Megias Vazquez, Diego author Cantón, Juan author García-Gutiérrez, Valentín author Murciano-Antón, María Aranzazu author Cervero, Miguel author Spivak, Adam author Planelles, Vicente author Coiras, Mayte author 2024-11 HIV-1 infection is efficiently controlled by the antiretroviral treatment (ART) but viral persistence in long-lived reservoirs formed by CD4 + T cells and macrophages impedes viral eradication and creates a chronic inflammatory environment. Dasatinib is a tyrosine kinase inhibitor clinically used against chronic myeloid leukemia (CML) that has also showed an anti-inflammatory potential. We previously reported that dasatinib is very efficient at interfering with HIV-1 infection of CD4 + T cells by preserving the antiviral activity of SAMHD1, an innate immune factor that blocks T-cell activation and proliferation and that is inactivated by phosphorylation at T592 (pSAMHD1). We observed that short-term treatment in vitro with dasatinib significantly reduced pSAMHD1 in monocyte-derived macrophages (MDMs) isolated from people with HIV (PWH) and healthy donors, interfering with HIV-1 infection. This inhibition was based on low levels of 2-LTR circles and proviral integration, while viral reverse transcription was not affected. MDMs isolated from people with CML on long-term treatment with dasatinib also showed low levels of pSAMHD1 and were resistant to HIV-1 infection. In addition, dasatinib decreased the inflammatory potential of MDMs by reducing the release of M1-related cytokines like TNFα, IL-1β, IL-6, CXCL8, and CXCL9, but preserving the antiviral activity through normal levels of IL-12 and IFNγ. Due to the production of M2-related anti-inflammatory cytokines like IL-1RA and IL-10 was also impaired, dasatinib appeared to interfere with MDMs differentiation. The use of dasatinib along with ART could be used against HIV-1 reservoir in CD4 and macrophages and to alleviate the chronic inflammation characteristic of PWH. Rodríguez-Mora S, Sánchez-Menéndez C, Bautista-Carrascosa G, Mateos E, Moreno-Serna L, Megías D, Cantón J, García-Gutiérrez V, Murciano-Antón MA, Cervero M, Spivak A, Planelles V, Coiras M. Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV. Biochem Pharmacol. 2024 Nov;229:116512. 10.1016/j.bcp.2024.116512 1873-2968 0006-2952 Biochemical pharmacology 39222713 https://hdl.handle.net/20.500.12105/26426 Chronic inflammation Dasatinib HIV-1 Monocyte-derived macrophages SAMHD1 Viral reservoir Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV