Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity <i>Ex Vivo</i> and <i>In Vivo</i>
Andrea Gramatica, Roland Schwarzer, William Brantley, Benjamin Varco-Merth, Hannah S. Sperber, Philip A. Hull, Mauricio Montaño, Stephen A. Migueles, Danielle M. Rosenthal, Louise E. Hogan, Jeffrey R. Johnson, Thomas Packard, Zachary W. Grimmett, Eytan Herzig, Emilie Besnard, Michael Nekorchuk, Feng Hsiao, Steven G. Deeks, Michael Snape, Bernard P. Kiernan, Nadia R. Roan, Jeffrey D. Lifson, Jacob D. Estes, Louis J. Picker, Eric Verdin, Nevan J. Krogan, Timothy J. Henrich, Mark Connors, Mélanie Ott, Satish K. Pillai, Afam A. Okoye, Warner C. Greene
Abstract
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.