title: TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species.
abstract: Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.
authors.affiliation: New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kirmaier
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.forename: Ruchi M
authors.initials: RM
authors.lastname: Newman
authors.forename: Laura R
authors.initials: LR
authors.lastname: Hall
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Morgan
authors.forename: Shelby
authors.initials: S
authors.lastname: O'Connor
authors.forename: Preston A
authors.initials: PA
authors.lastname: Marx
authors.forename: Mareike
authors.initials: M
authors.lastname: Meythaler
authors.forename: Simoy
authors.initials: S
authors.lastname: Goldstein
authors.forename: Alicia
authors.initials: A
authors.lastname: Buckler-White
authors.forename: Amitinder
authors.initials: A
authors.lastname: Kaur
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hirsch
authors.forename: Welkin E
authors.initials: WE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D016665:Cercocebus atys; D005838:Genotype; D008253:Macaca mulatta; D008992:Monkey Diseases / Q000635:transmission* / Q000821:virology; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000635:transmission* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity* / Q000502:physiology; D013045:Species Specificity; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases
references.citation: Curr Biol. 2006 Jan 10;16(1):95-100
references.pmid: 16401428
references.citation: J Med Primatol. 2003 Aug;32(4-5):180-6
references.pmid: 14498977
references.citation: J Virol. 2008 Dec;82(23):11682-94
references.pmid: 18799573
references.citation: J Virol. 2000 Oct;74(20):9388-95
references.pmid: 11000207
references.citation: Nat Struct Mol Biol. 2009 Oct;16(10):1036-42
references.pmid: 19767750
references.citation: Vaccine. 2005 Oct 10;23(42):4969-79
references.pmid: 16005121
references.citation: J Virol. 2004 Aug;78(16):8902-8
references.pmid: 15280498
references.citation: Cell. 1996 Dec 27;87(7):1285-94
references.pmid: 8980234
references.citation: J Virol. 2007 Sep;81(18):10201-6
references.pmid: 17609277
references.citation: Nature. 2002 Aug 8;418(6898):646-50
references.pmid: 12167863
references.citation: PLoS Pathog. 2009 Feb;5(2):e1000300
references.pmid: 19214216
references.citation: J Virol. 2008 Jul;82(14):7243-7
references.pmid: 18480454
references.citation: Virology. 1992 Feb;186(2):783-7
references.pmid: 1733112
references.citation: J Virol. 1988 Dec;62(12):4691-6
references.pmid: 2846880
references.citation: J Med Primatol. 1995 May;24(3):116-22
references.pmid: 8751050
references.citation: Retrovirology. 2006 Aug 22;3:54
references.pmid: 16925802
references.citation: Biochem Biophys Res Commun. 2005 Dec 30;338(4):1950-6
references.pmid: 16289103
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3569-74
references.pmid: 18287033
references.citation: AIDS Res Hum Retroviruses. 2004 Jul;20(7):772-87
references.pmid: 15307924
references.citation: Virology. 2006 Oct 10;354(1):15-27
references.pmid: 16887163
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3563-8
references.pmid: 18287034
references.citation: Science. 2000 Jan 28;287(5453):607-14
references.pmid: 10649986
references.citation: Mol Cell. 2004 Dec 22;16(6):849-59
references.pmid: 15610729
references.citation: AIDS. 2007 Dec;21 Suppl 8:S19-26
references.pmid: 18172386
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5514-9
references.pmid: 16540544
references.citation: PLoS Pathog. 2010 Jan 22;6(1):e1000738
references.pmid: 20107597
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2832-7
references.pmid: 15689398
references.citation: J Virol. 1999 Jun;73(6):4952-61
references.pmid: 10233957
references.citation: J Exp Med. 2008 Oct 27;205(11):2537-50
references.pmid: 18838548
references.citation: Science. 2006 Jul 28;313(5786):523-6
references.pmid: 16728595
references.citation: J Virol. 2006 Mar;80(5):2463-71
references.pmid: 16474153
references.citation: Science. 1985 Jun 7;228(4704):1201-4
references.pmid: 3159089
references.citation: J Virol. 2006 Jul;80(14):6738-44
references.pmid: 16809279
references.citation: J Virol. 2009 Jan;83(2):572-83
references.pmid: 18987149
references.citation: Science. 2000 Jun 9;288(5472):1789-96
references.pmid: 10846155
references.citation: Nature. 2008 Jan 24;451(7177):425-30
references.pmid: 18200009
references.citation: Curr Biol. 2005 Jan 11;15(1):73-8
references.pmid: 15649369
references.citation: J Virol. 2007 Aug;81(16):8827-32
references.pmid: 17537848
references.citation: PLoS Pathog. 2008 Feb 29;4(2):e1000003
references.pmid: 18389077
references.citation: J Virol. 1997 Feb;71(2):1608-20
references.pmid: 8995688
references.citation: PLoS Biol. 2004 Sep;2(9):E275
references.pmid: 15269786
references.citation: PLoS Pathog. 2007 Dec;3(12):e197
references.pmid: 18159944
references.citation: PLoS Biol. 2010 Feb 09;8(2):e1000301
references.pmid: 20161719
references.citation: J Virol. 2005 Jul;79(14):8969-78
references.pmid: 15994791
references.citation: Nature. 2004 Feb 26;427(6977):848-53
references.pmid: 14985764
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19134-9
references.pmid: 17142324
references.citation: J Virol. 2003 Feb;77(4):2736-40
references.pmid: 12552014
references.citation: Nat Rev Microbiol. 2005 Oct;3(10):799-808
references.pmid: 16175175
references.citation: AIDS. 2006 Feb 14;20(3):317-21
references.pmid: 16439864
references.citation: J Virol. 2006 May;80(10):5074-7
references.pmid: 16641299
references.citation: Syst Biol. 2002 Jun;51(3):528-35
references.pmid: 12079649
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13026-31
references.pmid: 15326293
references.citation: PLoS Pathog. 2008 Feb 8;4(2):e18
references.pmid: 18248091
references.citation: J Virol. 1991 Dec;65(12):7061-5
references.pmid: 1942258
references.citation: J Virol. 2009 Jun;83(11):5388-400
references.pmid: 19321617
references.citation: Front Biosci. 2004 Jan 01;9:225-54
references.pmid: 14766362
references.citation: J Virol. 2005 May;79(10):6111-21
references.pmid: 15857996
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3557-62
references.pmid: 18287035
references.citation: Retrovirology. 2005 Jun 20;2:40
references.pmid: 15967037
references.citation: J Virol. 2004 Jun;78(11):6005-12
references.pmid: 15140998