Journal
ANTIVIRAL RESEARCH
Volume 168, Issue -, Pages 18-27Publisher
ELSEVIER
DOI: 10.1016/j.antiviral.2019.05.003
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Funding
- Spanish Ministerio de Ciencia, Innovacion y Universidades [BFU2015-63800-R, RTI2018-094011-B100]
- Instituto de Salud Carlos III, Fondo de Investigacion Sanitaria (FIS) [PI17/00624, PI16/00103]
- FEDER
- Grifols
- Department of Economy and Knowledge of the Government of Catalonia
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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.
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