Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation

Alberto Bosque, Kyle A. Nilson, Amanda B. Macedo, Adam M. Spivak, Nancie M. Archin, Ryan M. Van Wagoner, Laura J. Martins, Camille L. Novis, Matthew A. Szaniawski, Chris M. Ireland, David M. Margolis, David H. Price, Vicente Planelles

Research output: Research - peer-reviewArticle

  • 2 Citations

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.

LanguageEnglish (US)
Pages1324-1334
Number of pages11
JournalCell Reports
Volume18
Issue number5
DOIs
StatePublished - Jan 31 2017

Fingerprint

Sumoylation
HIV-1
benzotriazole
HIV Long Terminal Repeat
Convulsive Therapy
Aptitude
Interleukin-2
Cell Proliferation
Cytokines
Viruses
T-Lymphocytes
Therapeutics
Direction compound
T-cells
Cell proliferation
Chemical activation
Derivatives
Molecules

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bosque, A., Nilson, K. A., Macedo, A. B., Spivak, A. M., Archin, N. M., Van Wagoner, R. M., ... Planelles, V. (2017). Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation. Cell Reports, 18(5), 1324-1334. DOI: 10.1016/j.celrep.2017.01.022

Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation. / Bosque, Alberto; Nilson, Kyle A.; Macedo, Amanda B.; Spivak, Adam M.; Archin, Nancie M.; Van Wagoner, Ryan M.; Martins, Laura J.; Novis, Camille L.; Szaniawski, Matthew A.; Ireland, Chris M.; Margolis, David M.; Price, David H.; Planelles, Vicente.

In: Cell Reports, Vol. 18, No. 5, 31.01.2017, p. 1324-1334.

Research output: Research - peer-reviewArticle

Bosque, A, Nilson, KA, Macedo, AB, Spivak, AM, Archin, NM, Van Wagoner, RM, Martins, LJ, Novis, CL, Szaniawski, MA, Ireland, CM, Margolis, DM, Price, DH & Planelles, V 2017, 'Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation' Cell Reports, vol 18, no. 5, pp. 1324-1334. DOI: 10.1016/j.celrep.2017.01.022
Bosque A, Nilson KA, Macedo AB, Spivak AM, Archin NM, Van Wagoner RM et al. Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation. Cell Reports. 2017 Jan 31;18(5):1324-1334. Available from, DOI: 10.1016/j.celrep.2017.01.022
Bosque, Alberto ; Nilson, Kyle A. ; Macedo, Amanda B. ; Spivak, Adam M. ; Archin, Nancie M. ; Van Wagoner, Ryan M. ; Martins, Laura J. ; Novis, Camille L. ; Szaniawski, Matthew A. ; Ireland, Chris M. ; Margolis, David M. ; Price, David H. ; Planelles, Vicente. / Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation. In: Cell Reports. 2017 ; Vol. 18, No. 5. pp. 1324-1334
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