Journal
CELL REPORTS
Volume 18, Issue 5, Pages 1324-1334Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.022
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Funding
- National Institute of Allergy and Infectious Diseases of the NIH [R21/R33 AI116212, U19 AI096113]
- National Institute of General Medical Sciences of the NIH [R01 GM35500]
- amfAR research grant [108014-49-RGRL]
- University of Iowa Presidential Graduate Fellowship
- National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under Ruth L. Kirschtein National Research Service [5T32 DK007115-40]
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The presence of latent HIV-1 in infected individuals represents a major barrier preventing viral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release. Mechanistic studies showed that benzotriazoles block SUMOylation of phosphorylated STAT5, increasing STAT5's activity and occupancy of the HIV-1 LTR. Our results identify benzotriazoles as latency reversing agents and STAT5 signaling and SUMOylation as targets for HIV-1 eradication strategies. These compounds represent a different direction in the search for shock and kill therapies.
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