The antiviral spectra of TRIM5α orthologues and human TRIM family proteins against lentiviral production.
BACKGROUND
Rhesus monkey TRIM5α (TRIM5αrh) recognizes the incoming HIV-1 core through its C-terminal B30.2(PRYSPRY) domain and promotes its premature disassembly or degradation before reverse transcription. Previously, we have shown that TRIM5αrh blocks HIV-1 production through the N-terminal RBCC domain by the recognition of Gag polyproteins. Although all TRIM family proteins have RBCC domains, it remains elusive whether they possess similar late-restriction activities.


RESULTS
We examined the antiviral spectra of TRIM5α orthologues and human TRIM family members which have a genetic locus proximal to human TRIM5α (TRIM5αhu), against primate lentiviral production. When HIV-1 virus-like particles (VLPs) were generated in the presence of TRIM5α proteins, rhesus, African green and cynomolgus monkey TRIM5α (TRIM5αag and TRIM5αcy), but not TRIM5αhu, were efficiently incorporated into VLPs, suggesting an interaction between HIV-1 Gag and TRIM5α proteins. TRIM5αrh potently restricted the viral production of HIV-1 groups M and O and HIV-2, but not simian lentiviruses including SIV(MAC)1A11, SIV(AGM)Tan-1 or SIV(AGM)SAB-1. TRIM5αhu did not show notable late restriction activities against these lentiviruses. TRIM5αag and TRIM5αcy showed intermediate restriction phenotypes against HIV-1 and HIV-2, but showed no restriction activity against SIV production. A series of chimeric TRIM5α constructs indicated that the N-terminal region of TRIM5αag and TRIM5αcy are essential for the late restriction activity, while the C-terminal region of TRIM5αcy negatively regulates the late restriction activity against HIV-1. When select human TRIM family proteins were examined, TRIM21 and 22 were efficiently incorporated into HIV-1 VLPs, while only TRIM22 reduced HIV-1 titers up to 5-fold. The antiviral activities and encapsidation efficiencies did not correlate with their relative expression levels in the producer cells.


CONCLUSIONS
Our results demonstrated the variations in the late restriction activities among closely related TRIM5α orthologues and a subset of human TRIM family proteins, providing further insights into the late restriction activities of TRIM proteins.
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Seiga
S
Ohmine
Ryuta
R
Sakuma
Toshie
T
Sakuma
Tayaramma
T
Thatava
Hiroaki
H
Takeuchi
Yasuhiro
Y
Ikeda
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D000090103:Antiviral Restriction Factors; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1; D000882:Haplorhini; D006801:Humans; D016086:Lentivirus; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014771:Virion / Q000737:chemistry; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D000998:Antiviral Agents; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11827-32
15280539
Virology. 2007 Sep 30;366(2):234-44
17543365
Virology. 2004 Sep 1;326(2):329-39
15321704
Virology. 2010 Dec 20;408(2):204-12
20956011
EMBO J. 1994 Jun 15;13(12):2935-47
8026477
AIDS Res Hum Retroviruses. 1999 May 20;15(8):707-12
10357466
EMBO J. 2001 May 1;20(9):2140-51
11331580
J Virol. 1995 Jul;69(7):4582-6
7769728
J Virol. 1992 Nov;66(11):6547-54
1404602
Nat Med. 2007 May;13(5):631-5
17435772
J Virol. 1992 Dec;66(12):7517-21
1433527
J Virol. 2007 Sep;81(18):10201-6
17609277
J Virol. 1996 Dec;70(12):8285-300
8970948
Virology. 2007 Apr 10;360(2):419-33
17156811
J Virol. 2005 Sep;79(18):11580-7
16140735
Virology. 2006 Sep 30;353(2):396-409
16828831
Proc Natl Acad Sci U S A. 1964 Jul;52:53-9
14192657
Biochem Biophys Res Commun. 2005 Dec 30;338(4):1950-6
16289103
Nat Med. 2008 Mar;14(3):235-6; author reply 236-8
18323834
J Virol. 1995 Mar;69(3):1755-61
7853514
AIDS Res Hum Retroviruses. 1992 Mar;8(3):395-402
1571198
Cell. 1996 Jun 28;85(7):1149-58
8674120
Proc Natl Acad Sci U S A. 2004 Oct 5;101 Suppl 2:14572-9
15310846
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10774-9
15249685
J Biol Chem. 2010 Feb 5;285(6):3784-3793
19951947
J Virol. 2004 Nov;78(21):11816-22
15479823
J Virol. 1999 Mar;73(3):2343-9
9971817
Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5514-9
16540544
J Virol. 2010 Jun;84(11):5790-801
20219908
Gene Ther. 2007 Jan;14(2):185-9
16943852
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10780-5
15249687
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2832-7
15689398
FEBS J. 2008 Apr;275(7):1540-1555
18312418
J Virol. 2007 Oct;81(19):10362-78
17626085
Eur J Immunol. 2008 Mar;38(3):619-30
18286572
J Immunol. 2009 Mar 15;182(6):3782-92
19265157
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10786-91
15249690
J Virol. 1998 Jul;72(7):5680-98
9621027
Nature. 1989 Jun 1;339(6223):389-92
2786147
J Virol. 1986 Aug;59(2):284-91
3016298
J Virol. 2008 Dec;82(23):11495-502
18799578
J Virol. 2005 Jul;79(14):8870-7
15994780
Virology. 1994 Nov 15;205(1):247-53
7975221
Curr Biol. 2005 Jan 11;15(1):73-8
15649369
Science. 2001 Feb 16;291(5507):1304-51
11181995
J Virol. 2005 Apr;79(7):3930-7
15767395
J Virol. 2005 Jul;79(14):8969-78
15994791
Nature. 2004 Feb 26;427(6977):848-53
14985764
Virology. 1997 Feb 17;228(2):394-9
9123848
J Virol. 1997 Mar;71(3):2107-13
9032343