Phase II study of the antiretroviral activity and safety of the glucocorticoid receptor antagonist mifepristone in HIV-1-infected patients

International Journal of Molecular Medicine

Volumn 28, Issue 3, 2011, Pages 437-442

  Donia, Marco ^a   Anzaldi, Massimiliano ^a   Di Marco, Roberto ^b   Libra, Massimo ^a   Mangano, Katia ^a   Fagone, Paolo ^a   Galvagna, Salvatore ^c   Di Gregorio, Pietro ^c   Nicoletti, Ferdinando ^a  

^a UNIVERSITY OF CATANIA   (Italy)

^b UNIVERSITY OF MOLISE   (Italy)

^c CANNIZZARO HOSPITAL   (Italy)

Author keywords

Cortisol; Glucocorticoid receptor; HIV; Mifepristone; Phase II; Viral protein r

Indexed keywords

ANTINEOPLASTIC AGENT; MIFEPRISTONE;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANTIVIRAL ACTIVITY; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CANCER CHEMOTHERAPY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CLINICAL ARTICLE; CLINICAL ASSESSMENT; CONTROLLED STUDY; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; GASTROINTESTINAL SYMPTOM; HERPES ZOSTER; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HYDROCORTISONE BLOOD LEVEL; HYPERGLYCEMIA; HYPOKALEMIA; IMMUNOLOGICAL PARAMETERS; MALE; NEOPLASM; OPEN STUDY; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; SIDE EFFECT; TREATMENT OUTCOME; VIRUS LOAD; WESTERN BLOTTING;

ADMINISTRATION, ORAL; ADULT; AGED; ANTI-HIV AGENTS; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CD4 LYMPHOCYTE COUNT; CD4-POSITIVE T-LYMPHOCYTES; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; FOLLOW-UP STUDIES; HIV INFECTIONS; HIV-1; HUMANS; MALE; MIDDLE AGED; MIFEPRISTONE; RECEPTORS, GLUCOCORTICOID; VIRAL LOAD; YOUNG ADULT;

EID: 79959958156     PISSN: 11073756     EISSN: 1791244X     Source Type: Journal    
DOI: 10.3892/ijmm.2011.703     Document Type: Article

References (33)

1. Connor RI, Chen BK, Choe S and Landau NR: Vpr is required for efficient replication of human immunodeficiency virus type 1 in mononuclear phagocytes. Virology 206: 935-944, 1995.
2. Hattori N, Michaels F, Fargnoli K, Marcon L, Gallo RC and Franchini G: The human immunodeficiency virus type 2 vpr gene is essential for productive infection of human macrophages. Proc Natl Acad Sci USA 87: 8080-8084, 1990.
3. Sherman MP, de Noronha CM, Eckstein LA, et at Nuclear export of Vpr is required for efficient replication of human immunodeficiency virus type 1 in tissue macrophages. J Virol 77: 7582-7589, 2003. (Pubitemid 36734528)
4. Schafer EA, Venkatachari NJ and Ayyavoo V: Antiviral effects of mifepristone on human immunodeficiency virus type-1 (HIV-I): targeting Vpr and its cellular partner, the glucocorticoid receptor (GR). Antiviral Res 72: 224-232, 2006.
5. Thieu KR Morrow MR Shedlock DJ et al: HIV-1 Vpr: regulator of viral survival (Review). Curr HIV Res 7: 153-162, 2009.
6. Goh WC, Rogel ME, Kinsey CM, et al: HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat Med 4: 65-71, 1998. (Pubitemid 28133081)
7. Ayyavoo V, Mahboubi A, Mahalingam S, et al: HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor κB. Nat Med 3: 1117-1123, 1997. (Pubitemid 27444453)
8. Subbramanian RA, Kessous-Elbaz A, Lodge R, et al: Human immunodeficiency virus type 1 Vpr is a positive regulator of viral transcription and infectivity in primary human macrophages. J Exp Med 187: 1103-1111, 1998. (Pubitemid 28176410)
9. Cohen EA, Terwilliger EF, Jalinoos Y, Proulx J, Sodroski JG and Haseltine WA: Identification of HIV-1 vpr product and function. J Acquir Immune Defic Syndr 3: 11-18, 1990. (Pubitemid 20062850)
10. Kino T, Gragerov A, Kopp JB, Stauber RH, Pavlakis GN and Chrousos GP: The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor. J Exp Med 189: 51-62, 1999.
11. Sawaya BE, Khalili K, Gordon J, Taube R and Amini S: Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome. J Biol Chem 275: 35209-35214, 2000.
12. Sherman MP, de Noronha CM, Pearce D and Greene WC: Human immunodeficiency virus type 1 Vpr contains two leucine-rich helices that mediate glucocorticoid receptor coactivation independently of its effects on G2 cell cycle arrest. J Virol 74: 8159-8165, 2000. (Pubitemid 30641662)
13. Paxton W, Connor RI and Landau NR: Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirement for the p6 region of gag and mutational analysis. J Virol 67: 7229-7237, 1993. (Pubitemid 23343849)
14. Popov S, Rexach M, Zybarth G, et al: Viral protein R regulates nuclear import of the HIV-1 pre-integration complex. EMBO J 17: 909-917, 1998. (Pubitemid 28077645)
15. Heinzinger NK, Bukinsky MI, Haggerty SA, et al: The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci USA 91: 7311-7315, 1994. (Pubitemid 24226853)
16. Vodicka MA, Koepp DM, Silver PA and Emerman M: HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev 12: 175-185, 1998. (Pubitemid 28060448)
17. Mirani M, Elenkov I, Volpi S, Hiroi N, Chrousos GP and Kino T: HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection. J Immunol 169: 6361-6368, 2002. (Pubitemid 36903484)
18. Levy DN, Refaeli Y, MacGregor RR and Weiner DB: Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 91: 10873-10877, 1994. (Pubitemid 24349587)
19. Muthumani K, Choo AY, Premkumar A et al: Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism. Cell Death Differ 1 (Suppl 1): S962-S970, 2005.
20. Lamberts SW, Koper JW and de Jong FH: The endocrine effects of long-term treatment with mifepristone (RU 486). J Clin Endocrinol Metab 73: 187-191, 1991. (Pubitemid 21901119)
21. Lamberts SW, Tanghe HL, Avezaat CJ, et al: Mifepristone (RU 486) treatment of meningiomas. J Neurol Neurosurg Psychiatry 55: 486-490, 1992.
22. Grunberg SM, Weiss MH, Spitz IM, et al: Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone. J Neurosurg 74: 861-866, 1991.
23. Rocereto TF, Saul HM, Aikins JA Jr and Paulson J: Phase II study of mifepristone (RU486) in refractory ovarian cancer. Gynecol Oncol 77: 429-423, 2000.
24. Johanssen S and Allolio B: Mifepristone (RU 486) in Cushing's syndrome. Eur J Endocrinol 157: 561-569, 2007.
25. Para MF, Schouten J Rosenkranz SL, et al: Phase I/II trial of the anti-HIV activity of mifepristone in HIV-infected subjects ACTG 5200. J Acquir Immune Defic Syndr 53: 491-495, 2010.
26. Bertagna X, Bertagna C, Luton JP, Husson JM and Girard F: The new steroid analog RU 486 inhibits glucocorticoid action in man. J Clin Endocrinol Metab 59: 25-28, 1984. (Pubitemid 14087519)
27. Bertagna X, Escourolle H, Pinquier JL, et al: Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral Cortisol deprivation. J Clin Endocrinol Metab 78: 375-380, 1994. (Pubitemid 24061756)
28. Healy DL, Chrousos GP, Schulte HM, et al: Pituitary and adrenal responses to the antiprogesterone and anti-glucocorticoid steroid RU 486 in primates. J Clin Endocrinol Metab 57: 863-865, 1983. (Pubitemid 13013550)
29. Gaillard RC, Riondel A, Muller AF, Herrmann W and Baulieu EE RU 486: a steroid with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day. Proc Natl Acad Sci USA 81: 3879-3882, 1984. (Pubitemid 14087822)
30. Spitz IM: Progesterone antagonists and progesterone receptor modulators: an overview. Steroids 68: 981-993, 2003.
31. Eisinger SH, Bonfiglio T, Fiscella K, Meldrum S and Guzick DS: Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas. J Minim Invasive Gynecol 12: 227-233, 2005. (Pubitemid 40800387)
32. Guo WX and Antakly T: AIDS-related Kaposi's sarcoma: evidence for direct stimulatory effect of glucocorticoid on cell proliferation. Am J Pathol 146: 727-734, 1995.
33. Martellotta F, Berretta M, Vaccher E, Schioppa O, Zanet E and Tirelli U: AIDS-related Kaposi's sarcoma: state of the art and therapeutic strategies. Curr HIV Res 7: 634-638, 2009.