Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains.
Vpu proteins of pandemic HIV-1 M strains degrade the viral receptor CD4 and antagonize human tetherin to promote viral release and replication. We show that Vpus from SIVgsn, SIVmus, and SIVmon infecting Cercopithecus primate species also degrade CD4 and antagonize tetherin. In contrast, SIVcpz, the immediate precursor of HIV-1, whose Vpu shares a common ancestry with SIVgsn/mus/mon Vpu, uses Nef rather than Vpu to counteract chimpanzee tetherin. Human tetherin, however, is resistant to Nef and thus poses a significant barrier to zoonotic transmission of SIVcpz to humans. Remarkably, Vpus from nonpandemic HIV-1 O strains are poor tetherin antagonists, whereas those from the rare group N viruses do not degrade CD4. Thus, only HIV-1 M evolved a fully functional Vpu following the three independent cross-species transmissions that resulted in HIV-1 groups M, N, and O. This may explain why group M viruses are almost entirely responsible for the global HIV/AIDS pandemic.
Sauter
Daniel
D
Institute of Molecular Virology, Universitätsklinikum, 89081 Ulm, Germany.
Schindler
Michael
M
Specht
Anke
A
Landford
Wilmina N
WN
Münch
Jan
J
Kim
Kyeong-Ae
KA
Votteler
Jörg
J
Schubert
Ulrich
U
Bibollet-Ruche
Frederic
F
Keele
Brandon F
BF
Takehisa
Jun
J
Ogando
Yudelca
Y
Ochsenbauer
Christina
C
Kappes
John C
JC
Ayouba
Ahidjo
A
Peeters
Martine
M
Learn
Gerald H
GH
Shaw
George
G
Sharp
Paul M
PM
Bieniasz
Paul
P
Hahn
Beatrice H
BH
Hatziioannou
Theodora
T
Kirchhoff
Frank
F
D000163:Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000821:virology; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015704:CD4 Antigens / Q000235:genetics*; D002460:Cell Line; D002521:Cercopithecus; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D015047:Zoonoses; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D015703:Antigens, CD; D015704:CD4 Antigens; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D008562:Membrane Glycoproteins; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C429284:NEF protein, SIV; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins