Dual effect of the broad spectrum kinase inhibitor midostaurin in acute and latent HIV-1 infection

Publication date: Available online 8 May 2019Source: Antiviral ResearchAuthor(s): Edurne Garcia-Vidal, Roger Badia, Maria Pujantell, Marc Castellví, Eudald Felip, Bonaventura Clotet, Eva Riveira-Muñoz, Ester Ballana, José A. EstéAbstractMidostaurin is a multi-kinase inhibitor with antineoplastic activity. We assessed the capacity of midostaurin to affect early and late steps of HIV-1 infection and to reactivate HIV-1 latently infected cells, alone or in combination with histone deacetylase inhibitors (HDACi) known to act as latency-reversing agents (LRA). Acute HIV-1 infection was assessed by flow cytometry in three cell types treated with midostaurin in the presence or absence of SAMHD1. Non-infected cells were treated with midostaurin and harvested for Western-Blot analysis. Macrophages infections were also quantified by quantitative RT-PCR. HIV-1 latency reactivation was assessed in several latency models. Midostaurin induced G2/M arrest and inhibited CDK2, preventing the phosphorylation of SAMHD1 associated to inhibition of its dNTPase activity. In the presence of SAMHD1, midostaurin blocked HIV-1 DNA formation and viral replication. However, following Vpx-mediated SAMHD1 degradation, midostaurin increased viral transcripts and replication. In three out of four HIV-1 latency models, including primary CD4+ T cells from, midostaurin effectively reversed HIV-1 latency and was synergistic in combination with LRA vorinostat and panobinostat. Our study describes a dual effe...
Source: Antiviral Therapy - Category: Virology Source Type: research