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

Edurne Garcia-Vidal, Roger Badia, Maria Pujantell, Marc Castellví, Eudald Felip, Bonaventura Clotet, Eva Riveira-Muñoz, Ester Ballana, José A. Esté

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Abstract

© 2019 Elsevier B.V. Midostaurin 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. Macrophage infections were also measured 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 virus replication. In three out of four HIV-1 latency models, including primary CD4 + T cells, midostaurin effectively reversed HIV-1 latency and was synergistic in combination with LRA vorinostat and panobinostat. Our study describes a dual effect for midostaurin in HIV-1 infection, antiviral or proviral depending on SAMHD1 activation, and highlights a role for active SAMHD1 in regulating the activity of potential HIV-1 latency reversal agents.
Original languageEnglish
Pages (from-to)18-27
JournalAntiviral Research
Volume168
DOIs
Publication statusPublished - 1 Aug 2019

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    Garcia-Vidal, E., Badia, R., Pujantell, M., Castellví, M., Felip, E., Clotet, B., Riveira-Muñoz, E., Ballana, E., & Esté, J. A. (2019). Dual effect of the broad spectrum kinase inhibitor midostaurin in acute and latent HIV-1 infection. Antiviral Research, 168, 18-27. https://doi.org/10.1016/j.antiviral.2019.05.003