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Viruses 2018, 10(7), 348; https://doi.org/10.3390/v10070348

Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products

1
Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
2
Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
3
Department of Chemistry, University of Colombo, Colombo 03, Sri Lanka
4
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
5
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada
Equal contribution.
*
Author to whom correspondence should be addressed.
Received: 13 June 2018 / Revised: 22 June 2018 / Accepted: 26 June 2018 / Published: 27 June 2018
(This article belongs to the Special Issue Homage to Mark Wainberg)
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Abstract

Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, aplysiatoxin, debromoaplysiatoxin, and previously-described alotaketal C) that induced expression of latent HIV-1 provirus in both cell line and primary cell models. Notably, aplysiatoxin induced similar levels of HIV-1 expression as prostratin but at up to 900-fold lower concentrations and without substantial effects on cell viability. Psammaplin A enhanced HIV-1 expression synergistically when treated in combination with the protein kinase C (PKC) activator prostratin, but not the histone deacetylase inhibitor (HDACi) panobinostat, suggesting that psammaplin A functions as a latency-reversing agent (LRA) of the HDACi class. Conversely, aplysiatoxin and debromoaplysiatoxin synergized with panobinostat but not prostratin, suggesting that they function as PKC activators. Our study identifies new compounds from previously untested marine natural products and adds to the repertoire of LRAs that can inform therapeutic “shock-and-kill”-based strategies to eliminate latent HIV-infected reservoirs. View Full-Text
Keywords: HIV-1; latency reversal; HIV reservoir; natural products; antivirals; shock-and-kill; psammaplin A; aplysiatoxin; debromoaplysiatoxin; alotaketal C HIV-1; latency reversal; HIV reservoir; natural products; antivirals; shock-and-kill; psammaplin A; aplysiatoxin; debromoaplysiatoxin; alotaketal C
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Richard, K.; Williams, D.E.; de Silva, E.D.; Brockman, M.A.; Brumme, Z.L.; Andersen, R.J.; Tietjen, I. Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products. Viruses 2018, 10, 348.

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