Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.
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.
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: abosque@gwu.edu.
Alberto
A
Bosque
Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
Kyle A
KA
Nilson
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Amanda B
AB
Macedo
Division of Infectious Diseases, Department of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
Adam M
AM
Spivak
UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Nancie M
NM
Archin
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Ryan M
RM
Van Wagoner
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Laura J
LJ
Martins
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Camille L
CL
Novis
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Matthew A
MA
Szaniawski
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Chris M
CM
Ireland
UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
David M
DM
Margolis
Molecular and Cellular Biology Program, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
David H
DH
Price
Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: vicente.planelles@path.utah.edu.
Vicente
V
Planelles
D000293:Adolescent; D049109:Cell Proliferation / Q000187:drug effects; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology; D058207:Sumoylation / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D054852:Small Molecule Libraries; D014230:Triazoles; C012771:benzotriazole
HIV-1 latency; HIV-1 reservoir; STAT5; SUMOylation; benzotriazoles; latency reversing agent; shock and kill