Ancient adaptive evolution of tetherin shaped the functions of Vpu and Nef in human immunodeficiency virus and primate lentiviruses.
Tetherin/BST-2 is a host-encoded protein that restricts a wide diversity of viruses at the stage of virion release. However, viruses have evolved antagonists of Tetherin, including the Vpu and Nef proteins of primate lentiviruses. Like other host genes subject to viral antagonism, primate Tetherin genes have evolved under positive selection. We show here that viral antagonists acting at three independent sites of selection have driven the evolution of Tetherin, with the strongest selective pressure on the cytoplasmic tail domain. Human Tetherin is unique among the Tetherins of simian primates in that it has a 5-amino-acid deletion that results in the loss of the residue under the strongest positive selection. We show that this residue at amino acid 17 is the site of the functional interaction of Tetherin with Nef, since single amino acid substitutions at this single position can determine the susceptibility of Tetherin to Nef antagonism. While the simian immunodeficiency viruses SIVcpz and SIVgor are able to antagonize their hosts' Tetherin with Nef, human immunodeficiency virus type 1 (HIV-1) Vpu has evolved to counteract Tetherin in humans. We mapped the adaptations in the N-terminal transmembrane domain of Vpu that allow it to counteract human Tetherin. Our combined evolutionary and functional studies have allowed us to reconstruct the host-pathogen interactions that have shaped Tetherin and its lentivirus-encoded antagonists.
Lim
Efrem S
ES
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, P.O. Box 10924, Seattle, WA 98109-1024, USA.
Malik
Harmit S
HS
Emerman
Michael
M
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017958:Lentiviruses, Primate / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011323:Primates / Q000821:virology*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D015693:Gene Products, nef; D054298:Human Immunodeficiency Virus Proteins; D008562:Membrane Glycoproteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
J Virol. 2009 Aug;83(15):7536-46
19474106
Curr HIV Res. 2008 May;6(3):200-8
18473783
Science. 1995 Nov 10;270(5238):988-91
7481804
J Virol. 1996 Feb;70(2):809-19
8551619
Science. 2006 Jul 28;313(5786):523-6
16728595
Bioinformatics. 2006 Dec 15;22(24):3096-8
17110367
Comput Appl Biosci. 1997 Oct;13(5):555-6
9367129
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3927-32
14978281
J Virol. 2003 Dec;77(23):12523-34
14610175
Cell. 2009 Oct 30;139(3):499-511
19879838
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3770-4
14999100
Traffic. 2003 Oct;4(10):694-709
12956872
Cell Host Microbe. 2008 Apr 17;3(4):245-52
18342597
J Virol. 1996 Dec;70(12):8285-300
8970948
PLoS Genet. 2009 Mar;5(3):e1000425
19300488
PLoS Pathog. 2009 May;5(5):e1000429
19436700
Cell Host Microbe. 2008 Jun 12;3(6):388-98
18541215
PLoS Pathog. 2009 Feb;5(2):e1000300
19214216
Retrovirology. 2010 Feb 18;7:13
20167081
J Interferon Cytokine Res. 2009 Sep;29(9):511-20
19694547
Cell Host Microbe. 2009 Jul 23;6(1):54-67
19501037
J Virol. 2009 Feb;83(4):1635-48
19073717
Virology. 1991 Dec;185(2):661-72
1683726
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2886-91
19179289
Mol Biol Evol. 2009 Dec;26(12):2865-75
19726537
PLoS Pathog. 2009 Sep;5(9):e1000574
19730691
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2832-7
15689398
AIDS Res Hum Retroviruses. 2009 Dec;25(12):1197-210
19929170
Mol Biol Evol. 2005 May;22(5):1208-22
15703242
Nature. 2006 Nov 9;444(7116):164
17093443
J Virol. 2007 Jul;81(14):7463-75
17494082
Cell Host Microbe. 2009 Nov 19;6(5):409-21
19917496
J Virol. 2009 Nov;83(22):11673-81
19726508
J Virol. 2009 Oct;83(19):9672-81
19605472
J Virol. 2009 Aug;83(16):7931-47
19515779
J Virol. 2009 Feb;83(4):1837-44
19036818
J Exp Med. 2009 Jul 6;206(7):1603-14
19564354
Nat Rev Microbiol. 2009 Jun;7(6):467-76
19305418
Genome Res. 2004 Jun;14(6):1188-90
15173120
Nature. 2008 Jan 24;451(7177):425-30
18200009
Cell Host Microbe. 2009 Aug 20;6(2):174-86
19683683
Cell. 2002 Feb 8;108(3):305-12
11853665
J Virol. 1999 Jul;73(7):5255-64
10364271
Virology. 2004 Feb 20;319(2):163-75
15015498
Cell Host Microbe. 2009 Mar 19;5(3):285-97
19286137
PLoS Biol. 2004 Sep;2(9):E275
15269786
PLoS Biol. 2010 Feb 09;8(2):e1000301
20161719
J Virol. 2009 Nov;83(22):11966-78
19740980
PLoS Pathog. 2009 May;5(5):e1000443
19461879
Philos Trans R Soc Lond B Biol Sci. 1995 Jun 29;348(1326):405-21
7480112
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2868-73
19196977
Annu Rev Genet. 2008;42:143-63
18624631
PLoS Pathog. 2009 May;5(5):e1000450
19478868
Nucleic Acids Res. 1997 Dec 15;25(24):4876-82
9396791
J Virol. 2009 Mar;83(5):2382-5
19091864
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20362-7
19075221