Format

Send to

Choose Destination
Cell Rep. 2017 Jan 31;18(5):1324-1334. doi: 10.1016/j.celrep.2017.01.022.

Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.

Author information

1
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: abosque@gwu.edu.
2
Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
3
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
4
Division of Infectious Diseases, Department of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
5
UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
6
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
7
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: vicente.planelles@path.utah.edu.

Abstract

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.

KEYWORDS:

HIV-1 latency; HIV-1 reservoir; STAT5; SUMOylation; benzotriazoles; latency reversing agent; shock and kill

PMID:
28147284
PMCID:
PMC5461578
DOI:
10.1016/j.celrep.2017.01.022
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center