Rapamycin blocks production of KSHV/HHV8: insights into the anti-tumor activity of an immunosuppressant drug.
BACKGROUND
Infection with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) often results in the development of fatal tumors in immunocompromised patients. Studies of renal transplant recipients show that use of the immunosuppressant drug rapamycin, an mTOR inhibitor, both prevents and can induce the regression of Kaposi's sarcoma (KS), an opportunistic tumor that arises within a subset of this infected population. In light of rapamycin's marked anti-KS activity, we tested whether the drug might directly inhibit the KSHV life cycle. We focused on the molecular switch that triggers this predominantly latent virus to enter the lytic (productive) replication phase, since earlier work links this transition to viral persistence and tumorigenesis.


RESULTS
In latently infected human B cell lines, we found that rapamycin inhibited entry of the virus into the lytic replication cycle, marked by a loss of expression of the lytic switch protein, replication and transcription activator (RTA). To test for viral-specific effects of rapamycin, we focused our studies on a B cell line with resistance to rapamycin-mediated growth inhibition. Using this line, we found that the drug had minimal effect on cell cycle profiles, cellular proliferation, or the expression of other cellular or latent viral proteins, indicating that the RTA suppression was not a result of global cellular dysregulation. Finally, treatment with rapamycin blocked the production of progeny virions.


CONCLUSIONS
These results indicate that mTOR plays a role in the regulation of RTA expression and, therefore, KSHV production, providing a potential molecular explanation for the marked clinical success of rapamycin in the treatment and prevention of post-transplant Kaposi's sarcoma. The striking inhibition of rapamycin on KSHV lytic replication, thus, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection.
Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia, United States of America.
Lisa A
LA
Nichols
Laura A
LA
Adang
Dean H
DH
Kedes
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000821:virology; D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000188:drug therapy; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Blood. 2000 Sep 15;96(6):2069-73
10979949
Ren Fail. 2007;29(1):103-5
17365918
J Heart Lung Transplant. 2006 Jun;25(6):726-9
16730579
Cell. 1992 Jun 26;69(7):1227-36
1377606
Cancer Res. 2006 Jan 1;66(1):168-74
16397229
Retrovirology. 2007 Apr 03;4:24
17407584
J Gen Virol. 2001 Feb;82(Pt 2):435-439
11161283
J Infect Dis. 1997 May;175(5):1198-201
9129085
J Virol. 1999 Nov;73(11):9348-61
10516043
Nucleic Acids Res. 1997 Mar 1;25(5):995-1001
9023110
Lancet. 1995 Sep 23;346(8978):799-802
7674745
J Virol. 2003 Sep;77(17):9669-84
12915579
Transplant Proc. 2005 Nov;37(9):3836-8
16386556
Blood. 2003 Jan 1;101(1):278-85
12393642
Science. 1992 Aug 14;257(5072):973-7
1380182
N Engl J Med. 2005 Mar 31;352(13):1317-23
15800227
Nature. 1999 Dec 23-30;402(6764):889-94
10622254
Blood. 2004 Mar 1;103(5):1632-4
14615380
J Cell Biol. 2003 Dec 8;163(5):931-6
14662739
J Cell Biochem. 2010 May;110(1):1-9
20213674
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4821-6
15047889
Transpl Int. 2003 Mar;16(3):202-6
12664217
Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):499-516
11313008
Nature. 1992 Jul 2;358(6381):70-3
1614535
Br J Haematol. 2006 Sep;134(5):475-84
16856892
J Virol. 2001 Feb;75(4):1857-63
11160684
J Virol. 2006 Oct;80(20):10073-82
17005685
Dermatology. 2006;213(1):30-3
16778423
Antimicrob Agents Chemother. 2002 Nov;46(11):3447-55
12384349
Curr Opin Cell Biol. 2005 Dec;17(6):596-603
16226444
Blood. 2001 May 15;97(10):3244-50
11342455
Oncogene. 2006 Oct 16;25(48):6423-35
17041627
J Virol. 2010 May;84(10):5260-9
20181700
PLoS Pathog. 2009 Mar;5(3):e1000334
19300492
Oncogene. 2007 Jul 26;26(34):4979-86
17310999
J Virol. 2005 May;79(9):5499-506
15827164
J Natl Cancer Inst. 1997 Dec 17;89(24):1868-74
9414174
J Virol. 1999 Mar;73(3):2232-42
9971806
J Immunol. 2007 Dec 15;179(12):8225-34
18056366
Cancer Res. 2006 Apr 1;66(7):3658-66
16585191
Sarcoma. 2008;2008:825093
18509482
J Clin Invest. 2004 Jan;113(1):124-36
14702116
Nat Med. 2003 Mar;9(3):300-6
12592400
Saudi J Kidney Dis Transpl. 2007 Nov;18(4):617-20
17951954
Nat Med. 1996 Mar;2(3):342-6
8612236
Cancer Res. 2003 Aug 1;63(15):4472-80
12907620
J Virol. 2003 Apr;77(7):4205-20
12634378
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10866-71
9724796
Ther Drug Monit. 1995 Dec;17(6):666-71
8588238
Mol Biol Cell. 2005 Oct;16(10):4648-59
16093351
Blood. 2007 Mar 1;109(5):2165-73
17082322
J Virol. 1999 Jul;73(7):5556-67
10364304
J Gen Virol. 1999 Jan;80 ( Pt 1):83-90
9934688
Cancer Cell. 2006 Aug;10(2):133-43
16904612
Transplantation. 2007 Apr 27;83(8):1114-21
17452903
Transplantation. 2009 Aug 27;88(4):597-8
19696647
Nat Rev Microbiol. 2008 Apr;6(4):266-75
18311165
Virology. 2009 Sep 15;392(1):34-51
19640558
J Virol. 2005 Mar;79(6):3479-87
15731242
J Biol Chem. 1999 Jan 15;274(3):1708-14
9880551
Cancer Res. 2000 Sep 1;60(17):4873-80
10987301
Cytometry. 1988 May;9(3):245-53
3378459
AIDS. 2000 May 5;14(7):899-902
10839602
J Virol. 1996 Jan;70(1):549-58
8523568
J Virol. 2006 Aug;80(16):7965-75
16873253
Int J Clin Pract. 2006 Nov;60(11):1509-12
16787440
Cell. 2006 Feb 10;124(3):471-84
16469695
J Virol. 2003 Jun;77(11):6188-96
12743275