Evaluating a new class of AKT/mTOR activators for HIV latency-reversing activity ex vivo and in vivo

Andrea Gramatica, Roland Schwarzer, William Brantley, Benjamin Varco-Merth, Hannah S. Sperber, Philip A. Hull, Mauricio Montano, Stephen A. Migueles, Danielle Rosenthal, Louise E. Hogan, Jeffrey R. Johnson, Thomas A. Packard, Zachary W. Grimmett, Eytan Herzig, Emilie Besnard, Michael Nekorchuk, Feng Hsiao, Steven G. Deeks, Michael Snape, Bernard KiernanNadia R. Roan, Jeffrey D. Lifson, Jacob D. Estes, Louis J. Picker, Eric Verdin, Nevan J. Krogan, Timothy J. Henrich, Mark Connors, Melanie Ott, Satish K. Pillai, Afam A. Okoye, Warner C. Greene

Research output: Contribution to journalArticlepeer-review

Abstract

An ability to activate latent human immunodeficiency virus type 1 (HIV- 1) expression could benefit many HIV cure strategies; however, most latency-reversing agents (LRAs) have proven disappointing. We evaluated AKT/mTOR activators as a potential new class of LRAs. Two glycogen synthase kinase-3 inhibitors (GSK-3i's), SB-216763 and tideglusib (the latter already in phase II clinical trials), that activate AKT/mTOR signaling were tested. These GSK-3i's reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy (ART) in the absence of T cell activation, release of inflammatory cytokines, cell toxicity, or impaired effector function of cytotoxic T lymphocytes or NK cells. However, when administered in vivo to simian immunodeficiency virus (SIV)-infected rhesus macaques on suppressive ART, tideglusib exhibited poor pharmacodynamic properties and resulted in no clear evidence of significant SIV latency reversal. Whether alternative pharmacological formulations or combinations of this drug with other classes of LRAs will lead to an effective in vivo latency-reversing strategy remains to be determined. Importance: If combined with immune therapeutics, latency-reversing agents (LRAs) have the potential to reduce the size of the reservoir sufficiently that an engineered immune response can control the virus in the absence of antiretroviral therapy. We have identified a new class of LRAs that do not induce T-cell activation and that are able to potentiate, rather than inhibit, CD81 T and NK cell cytotoxic effector functions. This new class of LRAs corresponds to inhibitors of glycogen synthase kinase- 3. In this work, we have also studied the effects of one member of this drug class, tideglusib, in SIV-infected rhesus monkeys. When tested in vivo, however, tideglusib showed unfavorable pharmacokinetic properties, which resulted in lack of SIV latency reversal. The disconnect between our ex vivo and in vivo results highlights the importance of developing novel LRAs with pharmacological properties that allow systemic drug delivery in relevant anatomical compartments harboring latent reservoirs.

Original languageEnglish (US)
Article numbere02393-20
JournalJournal of virology
Volume95
Issue number8
DOIs
StatePublished - Apr 2021

Keywords

  • HIV cure
  • HIV latency reversion
  • HIV-1
  • In vivo study
  • SIV

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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