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 Kiernan; Nadia 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

doi:10.1128/JVI.02393-20

Evaluating a New Class of AKT/mTOR Activators for HIV Latency Reversing Activity Ex Vivo and In Vivo

J Virol. 2021 Mar 25;95(8):e02393-20. doi: 10.1128/JVI.02393-20. Epub 2021 Feb 3.

Authors

Andrea Gramatica^{1

2}, Roland Schwarzer^{1

2}, William Brantley³, Benjamin Varco-Merth³, Hannah S Sperber^{4

5}, Philip A Hull¹, Mauricio Montano¹, Stephen A Migueles⁶, Danielle Rosenthal⁶, Louise E Hogan², Jeffrey R Johnson^{1

7}, Thomas A Packard¹, Zachary W Grimmett¹, Eytan Herzig^{1

2}, Emilie Besnard¹, Michael Nekorchuk³, Feng Hsiao^{1

8}, Steven G Deeks², Michael Snape⁹, Bernard Kiernan⁹, Nadia R Roan^{1

8}, Jeffrey D Lifson¹⁰, Jacob D Estes³, Louis J Picker³, Eric Verdin^{1

2

11}, Nevan J Krogan^{1

7}, Timothy J Henrich², Mark Connors⁶, Melanie Ott^{1

2

11}, Satish K Pillai^{12

4}, Afam A Okoye¹³, Warner C Greene^{14

2

11}

Affiliations

¹ Gladstone Institute of Virology, Gladstone Institutes, San Francisco, California, USA.
² Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
³ Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
⁴ Vitalant Research Institute, San Francisco, California, USA.
⁵ Free University of Berlin, Institute of Biochemistry, Berlin, Germany.
⁶ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
⁸ Department of Urology, University of California, San Francisco, San Francisco, California, USA.
⁹ AMO Pharma Ltd., London, United Kingdom.
¹⁰ AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
¹¹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
¹² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
¹³ Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA warner.greene@gladstone.ucsf.edu okoyea@ohsu.edu.
¹⁴ Gladstone Institute of Virology, Gladstone Institutes, San Francisco, California, USA warner.greene@gladstone.ucsf.edu okoyea@ohsu.edu.

Abstract

An ability to activate latent HIV-1 expression could benefit many HIV cure strategies, but the first generation of latency reversing agents (LRAs) has 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 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, CD8+ 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 next generation LRAs with pharmacological properties that allow systemic drug delivery in relevant anatomical compartments harboring latent reservoirs.

Abstract

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