Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency.

Affiliation

Schonhofer C(1), Yi J(1), Sciorillo A(2), Andrae-Marobela K(3), Cochrane A(4), Harris M(5), Brumme ZL(6), Brockman MA(7), Mounzer K(8), Hart C(2), Gyampoh K(2), Yuan Z(2), Montaner LJ(2), Tietjen I(9).
Author information:
(1)Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
(2)The Wistar Institute, Philadelphia, PA, USA.
(3)Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
(4)Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
(5)British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
(6)Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
(7)Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
(8)Jonathan Lax Immune Disorders Treatment Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA, USA.
(9)Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; The Wistar Institute, Philadelphia, PA, USA. Electronic address: [Email]

Abstract

While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persists in CD4+ T-cells that harbor latent but spontaneously inducible and replication-competent provirus. One strategy to inactivate these viral reservoirs involves the use of agents that continue to reinforce HIV latency even after their withdrawal. To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro. We found that, while all compounds inhibit provirus expression induced by latency-reversing agents in vitro, only aglycone flavonoids (chrysin, apigenin, luteolin, flavopiridol) and atuveciclib, but not the glycosylated flavonoid L7G, inhibit spontaneous latency reversal. Aglycone flavonoids and atuveciclib, but not L7G, also inhibit CDK9 and the HIV Tat protein. Aglycone flavonoids do not reinforce HIV latency following their in vitro withdrawal, which corresponds with their ability to also inhibit class I/II histone deacetylases (HDAC), a well-established mechanism of latency reversal. In contrast, atuveciclib and flavopiridol, which exhibit little or no HDAC inhibition, continue to reinforce latency for 9 to 14+ days, respectively, following their withdrawal in vitro. Finally, we show that flavopiridol also inhibits spontaneous ex vivo viral RNA production in CD4+ T cells from donors with HIV. These results implicate CDK9 inhibition (in the absence of HDAC inhibition) as a potentially favorable property in the search for compounds that durably reinforce HIV latency.