Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation

Cell Reports | January 31, 2017

Alberto Bosque, Kyle A. Nilson, Amanda B. Macedo, Adam M. Spivak et. al.
Cell Reports
DOI:  http://dx.doi.org/10.1016/j.celrep.2017.01.022

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Highlights:

  • Benzotriazoles reactivate and decrease latent HIV-1 both in vitro and ex vivo
  • Reactivation is independent of T cell proliferation or global immune activation
  • Inhibition of STAT5 SUMOylation is the main target of benzotriazoles
  • Benzotriazoles increase binding of STAT5 to the HIV-1 LTR

Summary:

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.