Details

Autor(en) / Beteiligte

• Rodríguez-Mora, Sara
• Sánchez-Menéndez, Clara
• Bautista-Carrascosa, Guiomar
• Mateos, Elena
• Moreno-Serna, Lucia
• Megías, Diego
• Cantón, Juan
• García-Gutiérrez, Valentín
• Murciano-Antón, María Aránzazu
• Cervero, Miguel
• Spivak, Adam
• Planelles, Vicente
• Coiras, Mayte

Titel

Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV

Ist Teil von

• Biochemical pharmacology, 2024-11, Vol.229, p.116512, Article 116512

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] 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.