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

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

  2. Author Address

    Gladstone Inst, Gladstone Inst Virol, San Francisco, CA 94158 USA.Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA.Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA.Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA.Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.Vitalant Res Inst, San Francisco, CA USA.Free Univ Berlin, Inst Biochem, Berlin, Germany.Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR 97006 USA.Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA.NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA.AMO Pharma Ltd, London, England.
    1. Year: 2021
    2. Date: Feb 03
  2. Journal: Journal of Virology
  3. AMER SOC MICROBIOLOGY,
    1. 95
    2. 8
  5. Type of Article: Article
  6. Article Number: e02393-20
  7. ISSN: 0022-538X
  1. 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.

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External Sources

  1. View Full Text
  2. DOI: 10.1128/JVI.02393-20
  3. PMID: 33536176
  4. View record in Web of Science®
  5. WOS: 000639294700006

Library Notes

  1. Fiscal Year: FY2020-2021
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