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The African natural product knipholone anthrone and its analogue anthralin (dithranol) enhance HIV-1 latency reversal
- Source :
- J Biol Chem
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- A sterilizing or functional cure for HIV is currently precluded by resting CD4(+) T cells that harbor latent but replication-competent provirus. The “shock-and-kill” pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple “shock-and-kill” agents, which in turn may inform ongoing LRA combination therapy efforts.
- Subjects :
- 0301 basic medicine
Drug Evaluation, Preclinical
HIV Infections
Pharmacology
Microbiology
Biochemistry
Jurkat Cells
03 medical and health sciences
Gene expression
Dithranol
medicine
Humans
Latency (engineering)
Molecular Biology
Protein kinase C
Anthracenes
030102 biochemistry & molecular biology
biology
Chemistry
Drug discovery
Cell Biology
Anthralin
Provirus
Virus Latency
030104 developmental biology
Histone
Cell culture
HIV-1
biology.protein
medicine.drug
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 295
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....c7f8467dd6ba3acba995e540db502016