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

• Published in: Viruses 2018-06, Vol.10 (7), p.348
• Main Authors: Richard, Khumoekae, Williams, David E, de Silva, E Dilip, Brockman, Mark A, Brumme, Zabrina L, Andersen, Raymond J, Tietjen, Ian
• Format: Article
• Language: English
• Subjects: alotaketal C; Anti-HIV Agents - isolation & purification; Anti-HIV Agents - pharmacology; antivirals; aplysiatoxin; Aquatic Organisms - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; CD4-Positive T-Lymphocytes - virology; Cell Line; Cell Survival - drug effects; Communication; debromoaplysiatoxin; Disulfides - pharmacology; Drug Discovery; High-Throughput Screening Assays; HIV Infections - virology; HIV reservoir; HIV-1; HIV-1 - drug effects; HIV-1 - physiology; Humans; latency reversal; natural products; Panobinostat - pharmacology; Phorbol Esters - pharmacology; Proviruses; psammaplin A; shock-and-kill; Tyrosine - analogs & derivatives; Tyrosine - pharmacology; Virus Activation - drug effects; Virus Latency - drug effects
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v10070348

Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established 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.