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Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains

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Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains Cell Host & Microbe Article Tetherin-Driven Adaptation of Vpu and Nef Function and the Evolution of Pandemic and Nonpandemic HIV-1 Strains Daniel Sauter,1,10 Michael Schindler,1,8,10 Anke Specht,1,10 Wilmina N. Landford,2 Jan Mu¨nch,1 Kyeong-Ae Kim,1 Jo¨ rg Votteler,3 Ulrich Schubert,3 Frederic Bibollet-Ruche,4 Brandon F. Keele,4,9 Jun Takehisa,4 Yudelca Ogando,2 Christina Ochsenbauer,4 John C. Kappes,4 Ahidjo Ayouba,5 Martine Peeters,5 Gerald H. Learn,4 George Shaw,4 Paul M. Sharp,6 Paul Bieniasz,2,7 Beatrice H. Hahn,4 Theodora Hatziioannou,2 and Frank Kirchhoff1,* 1Institute of Molecular Virology, Universita¨ tsklinikum, 89081 Ulm, Germany 2Aaron Diamond AIDS Research Center and Laboratory of Retrovirology, The Rockefeller University, 455 First Avenue, New York, NY 10016, USA 3University of Erlangen-Nuremberg, Institute of Clinical and Molecular Virology, Schlossgarten 4, 91054 Erlangen, Germany 4Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA 5Laboratoire Retrovirus UMR145, IRD and Universite Montpellier, 911 Avenue Agropolis, BP64501, 34034 Montpellier Cedex 5, France 6Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK 7Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, NY 10016, USA 8Present address: Heinrich-Pette-Institut, 20251 Hamburg, Germany 9Present address: The AIDS and Cancer Virus Program, Science Applications International, Corporation-Frederick Inc., National Cancer Institute, Frederick, MD 21702, USA 10These authors contributed equally to this work *Correspondence: [email protected] DOI 10.1016/j.chom.2009.10.004 SUMMARY present in the genomes of all primate lentiviruses. In contrast, vpu genes were initially only found in HIV-1 and its precursor Vpu proteins of pandemic HIV-1 M strains degrade SIVcpz from chimpanzees (Pan troglodytes), but not in HIV-2 the viral receptor CD4 and antagonize human tetherin or other SIV strains (Cohen et al., 1988; Huet et al., 1990; Gao to promote viral release and replication. We show that et al., 1999; Santiago et al., 2003). Subsequently, molecular Vpus from SIVgsn, SIVmus, and SIVmon infecting characterization of SIVs from additional primate species re- Cercopithecus primate species also degrade CD4 vealed that the genomes of SIVgsn, SIVmon, SIVden, and and antagonize tetherin. In contrast, SIVcpz, the SIVmus from greater spot-nosed (Cercopithecus nictitans), mona (C. mona), Dent’s mona (C. denti), and Mustached monkeys immediate precursor of HIV-1, whose Vpu shares (C. cephus), as well as SIVgor from gorillas (Gorilla gorilla gorilla), a common ancestry with SIVgsn/mus/mon Vpu, also carry vpu genes (Barlow et al., 2003; Courgnaud et al., uses Nef rather than Vpu to counteract chimpanzee 2002, 2003; Dazza et al., 2005; Takehisa et al., 2009). SIVcpz, tetherin. Human tetherin, however, is resistant to which gave rise to pandemic (M, main) and nonpandemic (O, Nef and thus poses a significant barrier to zoonotic outlier and N, non-M, non-O) groups of HIV-1 and also to SIVgor transmission of SIVcpz to humans. Remarkably, (which is closely related to HIV-1 O; Van Heuverswyn et al., 2006), Vpus from nonpandemic HIV-1 O strains are poor is the product of successive cross-species transmission and tetherin antagonists, whereas those from the rare recombination events involving precursors of today’s SIVgsn/ group N viruses do not degrade CD4. Thus, only mus/mon/den and SIVrcm from red-capped mangabeys HIV-1 M evolved a fully functional Vpu following the (Cercocebus torquatus)(Bailes et al., 2003). Thus, all vpu genes three independent cross-species transmissions that likely originated from a common ancestor of the SIVgsn/mus/ mon/den lineage of primate lentiviruses (Kirchhoff, 2009). resulted in HIV-1 groups M, N, and O. This may Vpu is an 80 amino acid integral class I membrane phospho- explain why group M viruses are almost entirely protein (Cohen et al., 1988; Maldarelli et al., 1993). Studies per- responsible for the global HIV/AIDS pandemic. formed with HIV-1 NL4-3 Vpu have established two main func- tions. First, Vpu induces the degradation of the primary viral INTRODUCTION receptor CD4 by a multistep process that involves direct binding of Vpu to the cytoplasmic tail of CD4 in the endoplasmic retic- Primate lentiviruses such as HIV and SIV encode several acces- ulum (Bour et al., 1995; Margottin et al., 1998; Willey et al., sory proteins. These include Vif, Vpr, Vpu, Vpx, and Nef and are 1992). Second, Vpu promotes the release of progeny virions often dispensable for viral growth in vitro. However, they are from HIV-1-infected human cells (Strebel et al., 1988; Klimkait important for viral replication in vivo because they counteract et al., 1990; Gottlinger et al., 1993) by antagonizing a recently host restriction factors, enhance viral replication and virion infec- identified restriction factor termed tetherin (also known as tivity, or facilitate viral evasion of the adaptive immune response CD317, BST2, or HM1.24) that is induced by interferon-a and (reviewed in Malim and Emerman, 2008). Vif, vpr, and nef are results in the ‘‘tethering’’ of nascent virions to the cellular plasma Cell Host & Microbe 6, 409–421, November 19, 2009 ª2009 Elsevier Inc. 409 Cell Host & Microbe Tetherin Antagonism by Primate Lentiviruses Positively charged Negatively charged Hydrophobic TM domain α-helix PP ”ß-turn” HIV-1 M NL4-3 MQPI----IVAIVALVVAIIIAIVVWSIV----IIEYRKILRQR----KIDRLIDR-LIERAEDSGNESEGEVSALVEMGVEMGHHAPWDIDDL HIV-1 M 89-6 MLSLQ---ILAIVALVVAAIIAIVVWSIV----FIEYRKILRQR----KIDRLIDR-IREREEDSGNESEGDQEELA-AL-ERGHLAPWDVDDL HIV-1 M YU-2 MQSLQ---VLAIVALVVATIIAIVVWTIV----FIEYRKILRQR----KIDRLINR-ITERAEDSGNESDGDQEELS-ALVERGHLAPWDVDDL HIV-1 M JR-CSF MQPLQ---ILAIVALVVAGIIAIIVWSIV----LIEYRKILRQR----KIDRLIDK-IRERAEDSGNESEGDQEELS-ALVERGHLAPWDINDL HIV-1 O 13127 MHYRD---LLTLIAISALLFANVVVWMFV-LKKYLEQKKQDRREK---EILKRLRR-LREKGDDSDYDSNGEEEQEVMDLVHSHGFDNPMFEL HIV-1 0 9435 MHYKD---LVIIIIISALLLVNVLIWMFN-LRKYLEQKEQERRER---EIIERLRR-IREIRDDSDYESNKEEEQEVMGLVHAHGFDNPMFEL HIV-1 O HJ001 MHNKD---LLIIIIVSALLLINVILWMFN-LRTYLKQKRQDRRER---EVIERIRR-IRQVREDSDYESNGEEEQEVMDLVHSHGFDNPMFEL HIV-1 N YBF30 MLS------LGFIALGAAVSIAVIVWALL----YREYKKIKLQE----KIKHIRQR-IREREEDSGNESDGDAEWLDGDEEWLVTLLSSSKLDQGNWV HIV-1 N 2693BA MLL------LGFIAVGIAIVIAAIIWVLL----YKEYKKIKLQE----KIRHIRQR-IKDRAEDSDSESDGDAEILATLLSPNKLDQGDWV HIV-1 N CK1.62 MLL------LGFIAVGIAIVIAVIIWVLL----YKEYKKIKLQE----EIKHIRQR-IKDRAEDSDSESDGDAEILATFLSPNKLDQGDWV SIVcpzPtt LB7 MD-LI---ELGLIGLVIELIIVIVVWLKA----YQLYKENIRQK----AINKLIER-IRERGEDSGNESEGDMDELHAILRSGD-PELVLIDN SIVcpzPtt MB66 MDIVQQ--VGLLVVLIIELVIVIVIWVKV----YKLCKEDRRQK----KIDRLIAR-IRERAEDSGNESDGDTEELQDLITEGDNLMHIGIRDNRNN SIVcpzPtt MB897 MEIFII---LGLIGIVIELVIAIVVWLKA----YECYKALKRQE----RRDQLIDR-IRERAEDSGNESDGDTEELEAILIPEDRHVLVAIRGY SIVcpzPtt EK505 MLLLIK---LGFIGLAIETLIVIVVWAIV----YRIYREVKVEE----KISQLRQR-IRDRAEDSGNESDGDAEEL-ANLLPPDRIDQDNWV SIVcpzPtt MT145 MQLEI----VLIILFIALMLVAIFAWIAA----YKEYKKLQQVR----RIERLQDR-IRSRAEDSGNESDGD-EILLVEELMQVHQHQVNPDWMDRILFW SIVcpzPtt GAB1 MTLLVG----LVLILVGLIAWNICIWGYIIKWGYRRYKR-HRLET---EIERLNLI-LRERAEDSGNESNGEEEERLEQLIHNYNHNNHFANPMFDL SIVcpzPts ANT MTNI-----FEYAFLAFSIVLWIICIPIL----YKLYKIYKQQQIDNKRNQRIIEVLSRRLSIDSAIEEDEE---ADTYYLGSGFANPVYREGDE SIVcpzPts TAN1 MIKIVVGSVSTNVIGILCILLILIGGGLLI--GIGIRRELERER----QHQRVLERLARRLSIDSGVEEDEE---FNWNNFDPHNYNPRDWI SIVcpzPts TAN2 MVKLVVGSVLTNVIGIFCILLILIGGGLLI--ITIIKREIERER----QHQRILERLIRRLSIDSGVEEDEE---LNWNNFDPHNYNPRDWI SIVcpzPts TAN3 MVKIVVGSVLTNVIGAFCILLILIGGGLLI--IAFVRRELERER----QHQRVIERLVRRLSIDSGIDEDEE---LNWNNFDPHNFNPRDWI SIVgor CP2139 MHPRD---IIVIIIGITLLAVTVIIWLKIFA-LYL RDRRER------RFFDRLERLLSNKEDEGYESNEEEAAELMEMGNELGFDFNLH SIVmon CML1 MNYWWS—LVAITYSLILIALPVAAWAWWR---YYKITKRFKRIDQ---EIQRLIQI-HERRRHDSGV-DTESESEQHEETHGFVNPVFNDDFGEWV SIVgsn 71 MSAAA---LWWWGAAVITFIYFCLAIFAL----YLAWDKWIKGKP---KIPVAVIR-LVEDDEESGIFEDAS-----SEPNAYGFANPGFEV SIVgsn 166 MHPAA---VWWWGAAIITFIYLCVALLAL----YLAWDKWVKGKP--KPTQVAVIR-LIEDEEDSGIYDDAS-----SELTGFNGFANPGFEV SIVmus 1085 MNYWY---LAAVIVTGIYFVIAIFAFVLA----YQRWCKPK-------KVEVSVIRLLEEGDGDSGIFEDAEDDMAESEHHAFANPAFEQ SIVmus S1239 MNYWY---LAAALVTGIYFLIALFAFVLA----YQRWCRP--------KVEVSVIRLLEEGDSDSGIFEDAEDEPNGDGHHAFANTAFEQ SIVmus S2500 MNWWW---FAAAVVTAIYFVIALVAFVLA----YQRWCQPQKGQ-----VEVNVIRLLEEGDTDSGIFEDAED-----GTDPAHGFLNPAFEL Figure 1. Alignment of HIV-1 and SIV Vpu Amino Acid Sequences The NL4-3 Vpu sequence is shown on top for comparison. The hydrophobic transmembrane (TM) domain, the central charged region, the position of two serine phosphorylation sites, and a b turn motif in the NL4-3 Vpu protein are indicated. Dashes indicate gaps introduced to optimize the alignment. Acidic residues (E, D) are highlighted in green; basic residues (K, R), blue; hydrophobic residues (I, V, L), orange; and residues that can potentially be phosphorylated (S, T, Y), red. membrane (Neil et al., 2008; Van Damme et al., 2008). Tetherin been an important prerequisite for the efficient spread of HIV-1 has a broad antiviral activity and inhibits the release of various group M in the human population. enveloped viruses (Jouvenet et al., 2009; Kaletsky et al., 2009; Sakuma et al., 2009). Furthermore, monkey and rodent tetherins RESULTS block virion release but are not counteracted by HIV-1 Vpu (Goffinet et al., 2009; Gupta et al., 2009; McNatt et al., 2009; Primate Lentiviral Vpus Are Highly Variable but Exhibit Wong et al., 2009). Some Conserved Features To date, functional data have almost exclusively been derived To examine
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