Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

Journal of Clinical Investigation

Volumn 127, Issue 2, 2017, Pages 651-656

  Martin, Alyssa R ^a   Pollack, Ross A ^a   Capoferri, Adam ^a,b   Ambinder, Richard F ^a   Durand, Christine M ^a   Siliciano, Robert F ^a,b  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOSPORIN A; GAMMA INTERFERON; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 6; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; RAPAMYCIN; TUMOR NECROSIS FACTOR; VIRUS RNA; CYTOKINE; MTOR PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE;

ANTIGEN RECOGNITION; ARTICLE; CELL PROLIFERATION; CELLULAR IMMUNITY; CONTROLLED STUDY; CYTOKINE RELEASE; CYTOTOXIC T LYMPHOCYTE; DOWN REGULATION; ENZYME INHIBITION; EX VIVO STUDY; GENE EXPRESSION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; IMMUNOMODULATION; PRIORITY JOURNAL; T LYMPHOCYTE ACTIVATION; VIRUS IMMUNITY; VIRUS INHIBITION; VIRUS LATENCY; VIRUS REACTIVATION; ANTAGONISTS AND INHIBITORS; CD4+ T LYMPHOCYTE; DRUG EFFECTS; ENZYMOLOGY; FEMALE; GENE EXPRESSION REGULATION; HIV INFECTIONS; MALE; METABOLISM; PATHOLOGY; PHYSIOLOGY; VIROLOGY; VIRUS ACTIVATION;

CD4-POSITIVE T-LYMPHOCYTES; CYTOKINES; FEMALE; GENE EXPRESSION REGULATION, VIRAL; HIV INFECTIONS; HIV-1; HUMANS; MALE; SIROLIMUS; TOR SERINE-THREONINE KINASES; VIRUS ACTIVATION; VIRUS LATENCY;

EID: 85014060688     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI89552     Document Type: Article

References (25)

1. Finzi D, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295-1300.
2. Chun TW, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997;94(24):13193-13197.
3. Siliciano JD, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9(6):727-728.
4. Archin NM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482-485.
5. Deeks SG. HIV: shock and kill. Nature. 2012;487(7408):439-440.
6. Prins JM, et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS. 1999;13(17):2405-2410.
7. Spivak AM, Planelles V. HIV-1 eradication: early trials (and tribulations). Trends Mol Med. 2016;22(1):10-27.
8. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014;20(4):425-429.
9. Isakov N, Altman A. Protein kinase C(theta) in T cell activation. Annu Rev Immunol. 2002;20:761-794.
10. Stach CS, Herrera A, Schlievert PM. Staphylococcal superantigens interact with multiple host receptors to cause serious diseases. Immunol Res. 2014;59(1-3):177-181.
11. Stebbings R, Eastwood D, Poole S, Thorpe R. After TGN1412: recent developments in cytokine release assays. J Immunotoxicol. 2013;10(1):75-82.
12. Williams SA, Greene WC. Regulation of HIV-1 latency by T-cell activation. Cytokine. 2007;39(1):63-74.
13. Chow CW, Rincón M, Davis RJ. Requirement for transcription factor NFAT in interleukin-2 expression. Mol Cell Biol. 1999;19(3):2300-2307.
14. Chan JK, Bhattacharyya D, Lassen KG, Ruelas D, Greene WC. Calcium/calcineurin synergizes with prostratin to promote NF-κB dependent activation of latent HIV. PLoS One. 2013;8(10):e77749.
15. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68.
16. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009;9(5):324-337.
17. Stock PG, et al. Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am J Transplant. 2014;14(5):1136-1141.
18. Krakauer T, Buckley M, Issaq HJ, Fox SD. Rapamycin protects mice from staphylococcal enterotoxin B-induced toxic shock and blocks cytokine release in vitro and in vivo. Antimicrob Agents Chemother. 2010;54(3):1125-1131.
19. Jones RB, et al. Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes. PLoS Pathog. 2014;10(8):e1004287.
20. Grybko MJ, Bartnik JP, Wurth GA, Pores-Fernando AT, Zweifach A. Calcineurin activation is only one calcium-dependent step in cytotoxic T lymphocyte granule exocytosis. J Biol Chem. 2007;282(25):18009-18017.
21. Araki K, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460(7251):108-112.
22. Laird GM, et al. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J Clin Invest. 2015;125(5):1901-1912.
23. Bosco MC, Rottschafer S, Taylor LS, Ortaldo JR, Longo DL, Espinoza-Delgado I. The antineoplastic agent bryostatin-1 induces proinflammatory cytokine production in human monocytes: synergy with interleukin-2 and modulation of interleukin-2Rγ chain expression. Blood. 1997;89(9):3402-3411.
24. Shan L, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36(3):491-501.
25. Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr Opin Immunol. 2004;16(5):550-557.