Advertisement

Subunit H of the V-ATPase Binds to the Medium Chain of Adaptor Protein Complex 2 and Connects Nef to the Endocytic Machinery*

Open AccessPublished:May 24, 2002DOI:https://doi.org/10.1074/jbc.M200522200
      Nef is an accessory protein of human and simian immunodeficiency viruses (HIV and SIV) that is required for efficient viral infectivity and pathogenicity. It decreases the expression of CD4 on the surface of infected cells. V1H is the regulatory subunit H of the vacuolar membrane ATPase (V-ATPase). Previously, the interaction between Nef and V1H has been found to facilitate the internalization of CD4, suggesting that V1H could connect Nef to the endocytic machinery. In this study, we demonstrate that V1H binds to the C-terminal flexible loop in Nef from HIV-1 and to the medium chain (μ2) of the adaptor protein complex 2 (AP-2) in vitro and in vivo. The interaction sites of V1H and μ2 were mapped to a central region in V1H from positions 133 to 363, which contains 4 armadillo repeats, and to the N-terminal adaptin-binding domain in μ2 from positions 1 to 145. Fusing Nef to V1H reproduced the appropriate trafficking of Nef. This chimera internalized CD4 even in the absence of the C-terminal flexible loop in Nef. Finally, blocking the expression of V1H decreased the enhancement of virion infectivity by Nef. Thus, V1H can function as an adaptor for interactions between Nef and AP-2.
      HIV-1
      human immunodeficiency virus type 1
      ARM repeat
      armadillo repeat (helical structure segment of approximately 42 residues)
      CCP
      clathrin-coated pits
      GST
      glutathione S-transferase
      V1H
      regulatory subunit H of the peripheral V1 domain of V-ATPases
      SIV
      simian immunodeficiency viruses
      AP-2
      adaptor protein complex 2
      HA
      hemagglutinin
      FACS
      fluorescence-activated cell sorter
      Nef is a 27–35-kDa myristoylated, membrane-associated protein encoded by primate lentiviruses (HIV-1,1 HIV-2 and SIV). It is expressed abundantly early in the viral replicative cycle (
      • Guatelli J.C.
      • Gingeras T.R.
      • Richman D.D.
      ,
      • Robert-Guroff M.
      • Popovic M.
      • Gartner S.
      • Markham P.
      • Gallo R.C.
      • Reitz M.S.
      ). By increasing levels of viremia Nef plays a critical role in viral pathogenesis and promotes the progression to AIDS (
      • Kestler III, H.W.
      • Ringler D.J.
      • Mori K.
      • Panicali D.L.
      • Sehgal P.K.
      • Daniel M.D.
      • Desrosiers R.C.
      ,
      • Kirchhoff F.
      • Greenough T.C.
      • Brettler D.B.
      • Sullivan J.L.
      • Desrosiers R.C.
      ,
      • Deacon N.J.
      • Tsykin A.
      • Solomon A.
      • Smith K.
      • Ludford-Menting M.
      • Hooker D.J.
      • McPhee D.A.
      • Greenway A.L.
      • Ellett A.
      • Chatfield C.
      • Lawson V.A.
      • Crowe S.
      • Maerz A.
      • Sonza S.
      • Learmont J.
      • Sullivan J.S.
      • Cunningham A.
      • Dwyer D.
      • Dowton D.
      • Mills J.
      ). In cell culture Nef enhances virion infectivity in a single round of replication (
      • Aiken C.
      • Trono D.
      ,
      • Schwartz O.
      • Marechal V.
      • Danos O.
      • Heard J.M.
      ). It also increases viral spread in some primary cell systems, in particular in co-cultures of immature dendritic cells with T cells (
      • Messmer D.
      • Ignatius R.
      • Santisteban C.
      • Steinman R.M.
      • Pope M.
      ,
      • Petit C.
      • Buseyne F.
      • Boccaccio C.
      • Abastado J.P.
      • Heard J.M.
      • Schwartz O.
      ,
      • Fackler O.T.
      • Wolf D.
      • Weber H.O.
      • Laffert B.
      • D'Aloja P.
      • Schuler-Thurner B.
      • Geffin R.
      • Saksela K.
      • Geyer M.
      • Peterlin B.M.
      • Schuler G.
      • Baur A.S.
      ). The mechanism of action of Nef, however, remains controversial. By interacting with molecules associated with the T cell antigen receptor, Nef activates infected cells (
      • Baur A.S.
      • Sawai E.T.
      • Dazin P.
      • Fantl W.J.
      • Cheng-Mayer C.
      • Peterlin B.M.
      ,
      • Fackler O.T.
      • Luo W.
      • Geyer M.
      • Alberts A.S.
      • Peterlin B.M.
      ,
      • Simmons A.
      • Aluvihare V.
      • McMichael A.
      ,
      • Wu Y.
      • Marsh J.W.
      ). Nef also decreases the expression of class I major histocompatibility complex determinants on the cell surface, thus protecting infected cells from cytotoxic T cells (
      • Schwartz O.
      • Marechal V.
      • Le Gall S.
      • Lemonnier F.
      • Heard J.M.
      ,
      • Collins K.L.
      • Chen B.K.
      • Kalams S.A.
      • Walker B.D.
      • Baltimore D.
      ). Finally, Nef internalizes CD4, which is the major receptor for HIV and SIV, thus preventing the superinfection of infected cells and interference with virus release and infectivity (
      • Benson R.E.
      • Sanfridson A.
      • Ottinger J.S.
      • Doyle C.
      • Cullen B.R.
      ,
      • Ross T.M.
      • Oran A.E.
      • Cullen B.R.
      ,
      • Lama J.
      • Mangasarian A.
      • Trono D.
      ). Because CD4 is also critical for host immune responses (
      • Parnes J.R.
      • Seong R.H.
      ), its absence on infected cells could contribute to the pathogenesis of AIDS. This variety of different functions is mediated by distinct sequence motifs within Nef (
      • Geyer M.
      • Fackler O.T.
      • Peterlin B.M.
      ).
      The internalization of CD4 by Nef results from increased rates of endocytosis (
      • Aiken C.
      • Konner J.
      • Landau N.R.
      • Lenburg M.E.
      • Trono D.
      ,
      • Bresnahan P.A.
      • Yonemoto W.
      • Ferrell S.
      • Williams-Herman D.
      • Geleziunas R.
      • Greene W.C.
      ,
      • Craig H.M.
      • Pandori M.W.
      • Guatelli J.C.
      ,
      • Greenberg M.
      • DeTulleo L.
      • Rapoport I.
      • Skowronski J.
      • Kirchhausen T.
      ,
      • Greenberg M.E.
      • Bronson S.
      • Lock M.
      • Neumann M.
      • Pavlakis G.N.
      • Skowronski J.
      ,
      • Lu X.
      • Yu H.
      • Liu S.H.
      • Brodsky F.M.
      • Peterlin B.M.
      ,
      • Piguet V.
      • Chen Y.L.
      • Mangasarian A.
      • Foti M.
      • Carpentier J.L.
      • Trono D.
      ). Indeed, binding between Nef and CD4 was demonstrated in the yeast two-hybrid system and in insect cells (
      • Harris M.P.
      • Neil J.C.
      ,
      • Rossi F.
      • Gallina A.
      • Milanesi G.
      ). Furthermore, NMR spectroscopy revealed that residues between positions 56 and 109 in Nef from HIV-1NL4-3 contact CD4 (
      • Grzesiek S.
      • Stahl S.J.
      • Wingfield P.T.
      • Bax A.
      ). Nef also increases the formation of clathrin-coated pits (CCP) (
      • Foti M.
      • Mangasarian A.
      • Piguet V.
      • Lew D.P.
      • Krause K.H.
      • Trono D.
      • Carpentier J.L.
      ) and co-localizes with adaptor protein (AP) complexes (
      • Greenberg M.E.
      • Bronson S.
      • Lock M.
      • Neumann M.
      • Pavlakis G.N.
      • Skowronski J.
      ), suggesting that Nef interacts directly with the endocytic machinery (
      • Bresnahan P.A.
      • Yonemoto W.
      • Ferrell S.
      • Williams-Herman D.
      • Geleziunas R.
      • Greene W.C.
      ,
      • Craig H.M.
      • Pandori M.W.
      • Guatelli J.C.
      ,
      • Greenberg M.
      • DeTulleo L.
      • Rapoport I.
      • Skowronski J.
      • Kirchhausen T.
      ,
      • Lu X.
      • Yu H.
      • Liu S.H.
      • Brodsky F.M.
      • Peterlin B.M.
      ,
      • Piguet V.
      • Chen Y.L.
      • Mangasarian A.
      • Foti M.
      • Carpentier J.L.
      • Trono D.
      ).
      Targeting of proteins to endosomes largely depends on specific sorting signals. They include the tyrosine-based motif, YXXφ, where X and φ are any and bulky hydrophobic amino acids, respectively, and the dileucine-based motif, LL or Lφ, which often is preceded by an acidic residue at position −4 (
      • Kirchhausen T.
      • Bonifacino J.S.
      • Riezman H.
      ). Both sorting motifs use distinct saturable components on adaptor protein complexes (
      • Kirchhausen T.
      • Bonifacino J.S.
      • Riezman H.
      ). For the tyrosine-based motif, the interaction is mediated by the medium chains of adaptor protein complexes. Indeed, Nef from SIV binds AP-2 via its N-terminal YXXL sequence (
      • Piguet V.
      • Chen Y.L.
      • Mangasarian A.
      • Foti M.
      • Carpentier J.L.
      • Trono D.
      ,
      • Mandic R.
      • Fackler O.T.
      • Geyer M.
      • Linnemann T.
      • Zheng Y.-H.
      • Peterlin B.M.
      ). Nef from HIV-1, however, lacks this N-terminal tyrosine-based motif but interacts with AP complexes via its C-terminal flexible loop, which contains a consensus dileucine-based motif (
      • Bresnahan P.A.
      • Yonemoto W.
      • Ferrell S.
      • Williams-Herman D.
      • Geleziunas R.
      • Greene W.C.
      ,
      • Craig H.M.
      • Pandori M.W.
      • Guatelli J.C.
      ,
      • Greenberg M.
      • DeTulleo L.
      • Rapoport I.
      • Skowronski J.
      • Kirchhausen T.
      ). This flexible loop also contains two diacidic amino acids, EE and DD, which are located 9 residues upstream and downstream, respectively, from the dileucine motif (
      • Geyer M.
      • Peterlin B.M.
      ,
      • Janvier K.
      • Craig H.
      • Le Gall S.
      • Benarous R.
      • Guatelli J.
      • Schwartz O.
      • Benichou S.
      ). The downstream motif, which is highly conserved among different nef alleles, is required for the internalization of CD4 by Nef as well as for its interaction with the subunit H of the vacuolar membrane ATPase, V1H (
      • Lu X.
      • Yu H.
      • Liu S.H.
      • Brodsky F.M.
      • Peterlin B.M.
      ,
      • Mandic R.
      • Fackler O.T.
      • Geyer M.
      • Linnemann T.
      • Zheng Y.-H.
      • Peterlin B.M.
      ,
      • Geyer M.
      • Peterlin B.M.
      ,
      • Janvier K.
      • Craig H.
      • Le Gall S.
      • Benarous R.
      • Guatelli J.
      • Schwartz O.
      • Benichou S.
      ).
      This study focuses on V1H, which is the 56-kDa regulatory subunit H of the universal proton pump (
      • Stevens T.H.
      • Forgac M.
      ,
      • Nishi T.
      • Forgac M.
      ). The V-ATPase is required for the acidification of endosomes and lysosomes and binds AP-2 (
      • Stevens T.H.
      • Forgac M.
      ,
      • Mellman I.
      • Fuchs R.
      • Helenius A.
      ). Thus, V1H could be a connector for Nef, which would carry CD4 from CCP to lysosomes for its degradation. To this end, we performed binding and internalization studies, which revealed that V1H binds Nef and the μ-chain of AP-2 in vitro and in vivo. In addition, when the C-terminal flexible loop in Nef was mutated or deleted, V1H fused to this truncated Nef protein could perform all the internalization functions of its wild-type counterpart. These findings fulfilled the structural and functional criteria for V1H as an adaptor between Nef and AP-2. Additionally, our results suggest that V1H plays a central role in the enhancement of virion infectivity by Nef.

      DISCUSSION

      In this study, we demonstrated that the regulatory subunit H of the V-ATPase binds the C-terminal flexible loop in Nef and the medium chain (μ2) of the adaptor protein complex AP-2. Thus, V1H can connect Nef and CD4 to the endocytic machinery. Direct and specific interactions between Nef and V1H, as well as V1H, and the μ2 chain could be demonstrated in vitro and in vivo. Importantly, binding sites on Nef, which bind CD4 and V1H, were separable so that distinct surfaces on Nef lacking the flexible loop, when fused to V1H, could still internalize CD4. To this end, we performed kinetic internalization assays on the receptor and Nef or fusion proteins between Nef and V1H. Indeed, Nef and V1H were found to traffic similarly to each other, which depended on the flexible loop in Nef. Finally, blocking the expression of V1H and thus the function of the V-ATPase decreased the infectivity of HIV.
      Importantly, Nef and V1H decreased steady-state levels and increased rates of internalization of CD8 equivalently (Figs. 1 and 2). In the presence of only the N-terminal 160 residues of Nef, the hybrid mutant Nef160-V1H protein was also able to target CD4 as efficiently as the wild-type Nef protein. Thus, V1H was able to perform the function of the flexible loop in Nef, and the remainder of Nef was sufficient to bind to CD4. This finding is in complete agreement with structural studies between Nef and CD4 (
      • Grzesiek S.
      • Stahl S.J.
      • Wingfield P.T.
      • Bax A.
      ) and reconciles the severe defect in the internalization of CD4, which was observed with the mutant NefED-AA protein (
      • Lu X.
      • Yu H.
      • Liu S.H.
      • Brodsky F.M.
      • Peterlin B.M.
      ). Moreover, as reflected in the steady-state levels of CD4 and CD8, no significant recycling was observed with Nef or V1H fusion proteins.
      Binding studies performed with GST-V1H fusion proteins and in vitro translated μ2 demonstrated that a central region of four ARM repeats of V1H interacts with the N-terminal domain in μ2 (Fig.5). Both protein fragments were stable and expressed to similar levels, which indicated a domain-domain protein interaction. The ARM or HEAT repeat superfold is composed of tandemly arranged helical repeats that form an elongated shaped molecule (
      • Conti E.
      • Izaurralde E.
      ). This fold is known already from other proteins that are involved in intracellular trafficking processes, such as Importin α and β or β-Catenin. Its structural feature allows for sequence motif recognition by its concave surface and simultaneous assembly into multisubunit complexes. As an example, the binding site on Importin β for the small GTP-binding protein Ran does not overlap with its binding sites for the FxFG nucleoporin repeats but may instead generate a conformational change in the molecule (
      • Bayliss R.
      • Littlewood T.
      • Stewart M.
      ). Indeed, from structural studies ARM and HEAT repeat containing proteins are known to be very flexible and change its conformation upon variable protein complex formations (
      • Conti E.
      • Izaurralde E.
      ).
      By interacting with the N-terminal domain of μ2-(1–145), its ability to bind tyrosine-based sorting motifs for cargo uptake was not blocked. This suggests that a fully functional adaptor protein complex was preserved. However, we cannot exclude at this point that V1H might also substitute for the β-chain of the adaptor protein complex by its binding to μ2, generating thereby a complex with specific trafficking features. Because V1H is supposed to bind both V1 and V0 sectors of the vacuolar ATPase (
      • Xu T.
      • Vasilyeva E.
      • Forgac M.
      ,
      • Zhou Z.
      • Peng S.B.
      • Crider B.P.
      • Andersen P.
      • Xie X.S.
      • Stone D.K.
      ), its interaction with the adaptor protein complexes could also be important for the assembly of two ATPase sectors. Indeed, by its interaction with AP-2, V1H could also connect the V-ATPase to clathrin (
      • Foti M.
      • Mangasarian A.
      • Piguet V.
      • Lew D.P.
      • Krause K.H.
      • Trono D.
      • Carpentier J.L.
      ,
      • Myers M.
      • Forgac M.
      ,
      • Liu Q.
      • Feng Y.
      • Forgac M.
      ). With its binding to the flexible loop of Nef, V1H could thus function as an adaptor protein to mediate trafficking of CD4 and Nef to endosomes and lysosomes and thereby circumvent the transfer of cargo from adaptor complexes to coatomers (
      • Janvier K.
      • Craig H.
      • Le Gall S.
      • Benarous R.
      • Guatelli J.
      • Schwartz O.
      • Benichou S.
      ). A model that displays the assembly of AP-2 complexes, the V-ATPase and clathrin at the plasma membrane, and the Nef-mediated internalization of CD4 is shown in Fig.7. The display of the V-ATPase is based on the latest models by electron microscopy (
      • Wilkens S.
      • Forgac M.
      ,
      • Domgall I.
      • Venzke D.
      • Luttge U.
      • Ratajczak R.
      • Bottcher B.
      ).
      Figure thumbnail gr7
      Figure 7Proposed model of the interactions between AP-2 , V-ATPase, and clathrin to stimulate Nef-mediated CD4 internalization. The myristoylated HIV-1 Nef protein interacts with the cytoplasmic tail of CD4 molecules at the plasma membrane and stimulates its internalization. The interaction of AP-2 with clathrin leads to formation of clathrin-coated vesicles (
      • Kirchhausen T.
      • Bonifacino J.S.
      • Riezman H.
      ). Subunit H of the vacuolar (H+)-ATPase (V1H) interacts with the peripheral V1 and the integral V0 sector to regulate its proton pump activity (
      • Zhou Z.
      • Peng S.B.
      • Crider B.P.
      • Andersen P.
      • Xie X.S.
      • Stone D.K.
      ,
      • Nishi T.
      • Forgac M.
      ). V1H binds μ2 of AP-2 to recruit the V-ATPase into clathrin-coated pits. Thus, via the interaction with Nef, V1H enhances the internalization of CD4 to endosomal and lysosomal compartments.
      Our results argue for an important role of the interaction between Nef and V1H for the enhancement of virion infectivity. This scenario is similar to that for SIV, where binding of Nef to V1H also correlated with the increased infectivity of virus particles (
      • Mandic R.
      • Fackler O.T.
      • Geyer M.
      • Linnemann T.
      • Zheng Y.-H.
      • Peterlin B.M.
      ). Importantly, as the involvement of V1H is observed in the absence of CD4 in the virus-producing cells, these results differ from effects that are reported for high levels of CD4 (
      • Ross T.M.
      • Oran A.E.
      • Cullen B.R.
      ,
      • Lama J.
      • Mangasarian A.
      • Trono D.
      ). Thus, albeit the binding of V1H to the flexible loop in Nef facilitated the internalization of CD4, it also affected virion infectivity independently of CD4. What could be the mechanism of this effect of V1H? Consistent with the previous observation that the increase of virion infectivity by Nef is imprinted on the particle in the producing cell, our recent findings suggest that Nef acts as a chaperone of virus production by recruiting the assembly of HIV into lipid rafts (
      • Miller M.D.
      • Warmerdam M.T.
      • Page K.A.
      • Feinberg M.A.
      • Greene W.C.
      ,
      • Fackler O.T.
      • d′Aloja P.
      • Baur A.S.
      • Federico M.
      • Peterlin B.M.
      ,
      • Zheng Y.
      • Plemenitas A.
      • Linnemann T.
      • Fackler O.T.
      • Peterlin B.M.
      ). Because the V-ATPase plays important roles in both endocytic and secretory transport (
      • Stevens T.H.
      • Forgac M.
      ,
      • Nishi T.
      • Forgac M.
      ), the adaptor function of V1H could facilitate the proper trafficking of a complex between Nef and viral structural proteins to the plasma membrane and their partitioning into lipid rafts, where local rearrangements of the actin cytoskeleton might facilitate particle release (
      • Fackler O.T.
      • Luo W.
      • Geyer M.
      • Alberts A.S.
      • Peterlin B.M.
      ,
      • Fackler O.T.
      • Lu X.
      • Frost J.A.
      • Geyer M.
      • Jiang B.
      • Luo W.
      • Abo A.
      • Alberts A.S.
      • Peterlin B.M.
      ). As for CD4 down-regulation, it is unclear whether this would occur with or without involvement of the entire V-ATPase and its catalytic activity. Although it might be plausible that the recruitment of the V-ATPase could help to optimize the local pH that is required for the maturation of virus particles, no effect of Nef on maturation per se has been observed (
      • Miller M.D.
      • Warmerdam M.T.
      • Page K.A.
      • Feinberg M.A.
      • Greene W.C.
      ,
      • Gross I.
      • Hohenberg H.
      • Wilk T.
      • Wiegers K.
      • Grattinger M.
      • Müller B.
      • Fuller S.
      • Kräusslich H.G.
      ). Alternatively, Nef and V1H might trigger the internalization of yet unidentified cell surface receptors that counteract virion infectivity by mechanisms similar to CD4 down-regulation. These strategies might represent a variation on a common theme employed by other viruses such as HTLV-I and papillomaviruses that also engage the V-ATPase (
      • Collins K.L.
      • Chen B.K.
      • Kalams S.A.
      • Walker B.D.
      • Baltimore D.
      ,
      • Franchini G.
      • Mulloy J.C.
      • Koralnik I.J.
      • Lo
      • Monico A.
      • Sparkowski J.J.
      • Andresson T.
      • Goldstein D.J.
      • Schlegel R.
      ,
      • Goldstein D.J.
      • Finbow M.E.
      • Andresson T.
      • McLean P.
      • Smith K.
      • Bubb V.
      • Schlegel R.
      ,
      • Koralnik I.J.
      • Mulloy J.C.
      • Andresson T.
      • Fullen J.
      • Franchini G.
      ). Unraveling further details of the underlying mechanism will not only help us to understand viral pathogenesis, but also yield important insights into the role of the V-ATPase and its individual subunits in intracellular trafficking processes.

      Acknowledgments

      We thank John Guatelli and Juan Bonifacino for plasmids and Judith Gasteier for help with in vitro translation.

      REFERENCES

        • Guatelli J.C.
        • Gingeras T.R.
        • Richman D.D.
        J. Virol. 1990; 64: 4093-4098
        • Robert-Guroff M.
        • Popovic M.
        • Gartner S.
        • Markham P.
        • Gallo R.C.
        • Reitz M.S.
        J. Virol. 1990; 64: 3391-3398
        • Kestler III, H.W.
        • Ringler D.J.
        • Mori K.
        • Panicali D.L.
        • Sehgal P.K.
        • Daniel M.D.
        • Desrosiers R.C.
        Cell. 1991; 65: 651-662
        • Kirchhoff F.
        • Greenough T.C.
        • Brettler D.B.
        • Sullivan J.L.
        • Desrosiers R.C.
        N. Engl. J. Med. 1995; 332: 228-232
        • Deacon N.J.
        • Tsykin A.
        • Solomon A.
        • Smith K.
        • Ludford-Menting M.
        • Hooker D.J.
        • McPhee D.A.
        • Greenway A.L.
        • Ellett A.
        • Chatfield C.
        • Lawson V.A.
        • Crowe S.
        • Maerz A.
        • Sonza S.
        • Learmont J.
        • Sullivan J.S.
        • Cunningham A.
        • Dwyer D.
        • Dowton D.
        • Mills J.
        Science. 1995; 270: 988-991
        • Aiken C.
        • Trono D.
        J. Virol. 1995; 69: 5048-5056
        • Schwartz O.
        • Marechal V.
        • Danos O.
        • Heard J.M.
        J. Virol. 1995; 69: 4053-4059
        • Messmer D.
        • Ignatius R.
        • Santisteban C.
        • Steinman R.M.
        • Pope M.
        J. Virol. 2000; 74: 2406-2413
        • Petit C.
        • Buseyne F.
        • Boccaccio C.
        • Abastado J.P.
        • Heard J.M.
        • Schwartz O.
        Virology. 2001; 286: 225-236
        • Fackler O.T.
        • Wolf D.
        • Weber H.O.
        • Laffert B.
        • D'Aloja P.
        • Schuler-Thurner B.
        • Geffin R.
        • Saksela K.
        • Geyer M.
        • Peterlin B.M.
        • Schuler G.
        • Baur A.S.
        Curr. Biol. 2001; 11: 1294-1299
        • Baur A.S.
        • Sawai E.T.
        • Dazin P.
        • Fantl W.J.
        • Cheng-Mayer C.
        • Peterlin B.M.
        Immunity. 1994; 1: 373-384
        • Fackler O.T.
        • Luo W.
        • Geyer M.
        • Alberts A.S.
        • Peterlin B.M.
        Mol. Cell. 1999; 3: 729-739
        • Simmons A.
        • Aluvihare V.
        • McMichael A.
        Immunity. 2001; 14: 763-777
        • Wu Y.
        • Marsh J.W.
        Science. 2001; 293: 1503-1506
        • Schwartz O.
        • Marechal V.
        • Le Gall S.
        • Lemonnier F.
        • Heard J.M.
        Nat. Med. 1996; 2: 338-342
        • Collins K.L.
        • Chen B.K.
        • Kalams S.A.
        • Walker B.D.
        • Baltimore D.
        Nature. 1998; 391: 397-401
        • Benson R.E.
        • Sanfridson A.
        • Ottinger J.S.
        • Doyle C.
        • Cullen B.R.
        J. Exp. Med. 1993; 177: 1561-1566
        • Ross T.M.
        • Oran A.E.
        • Cullen B.R.
        Curr. Biol. 1999; 9: 613-621
        • Lama J.
        • Mangasarian A.
        • Trono D.
        Curr. Biol. 1999; 9: 622-631
        • Parnes J.R.
        • Seong R.H.
        Semin. Immunol. 1994; 6: 221-229
        • Geyer M.
        • Fackler O.T.
        • Peterlin B.M.
        EMBO Rep. 2001; 2: 580-585
        • Aiken C.
        • Konner J.
        • Landau N.R.
        • Lenburg M.E.
        • Trono D.
        Cell. 1994; 76: 853-864
        • Bresnahan P.A.
        • Yonemoto W.
        • Ferrell S.
        • Williams-Herman D.
        • Geleziunas R.
        • Greene W.C.
        Curr. Biol. 1998; 8: 1235-1238
        • Craig H.M.
        • Pandori M.W.
        • Guatelli J.C.
        Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11229-11234
        • Greenberg M.
        • DeTulleo L.
        • Rapoport I.
        • Skowronski J.
        • Kirchhausen T.
        Curr. Biol. 1998; 8: 1239-1242
        • Greenberg M.E.
        • Bronson S.
        • Lock M.
        • Neumann M.
        • Pavlakis G.N.
        • Skowronski J.
        EMBO J. 1997; 16: 6964-6976
        • Lu X.
        • Yu H.
        • Liu S.H.
        • Brodsky F.M.
        • Peterlin B.M.
        Immunity. 1998; 8: 647-656
        • Piguet V.
        • Chen Y.L.
        • Mangasarian A.
        • Foti M.
        • Carpentier J.L.
        • Trono D.
        EMBO J. 1998; 17: 2472-2481
        • Harris M.P.
        • Neil J.C.
        J. Mol. Biol. 1994; 241: 136-142
        • Rossi F.
        • Gallina A.
        • Milanesi G.
        Virology. 1996; 217: 397-403
        • Grzesiek S.
        • Stahl S.J.
        • Wingfield P.T.
        • Bax A.
        Biochemistry. 1996; 35: 10256-10261
        • Foti M.
        • Mangasarian A.
        • Piguet V.
        • Lew D.P.
        • Krause K.H.
        • Trono D.
        • Carpentier J.L.
        J. Cell Biol. 1997; 139: 37-47
        • Kirchhausen T.
        • Bonifacino J.S.
        • Riezman H.
        Curr. Opin. Cell Biol. 1997; 9: 488-495
        • Mandic R.
        • Fackler O.T.
        • Geyer M.
        • Linnemann T.
        • Zheng Y.-H.
        • Peterlin B.M.
        Mol. Biol. Cell. 2001; 12: 463-473
        • Geyer M.
        • Peterlin B.M.
        FEBS Lett. 2001; 496: 91-95
        • Janvier K.
        • Craig H.
        • Le Gall S.
        • Benarous R.
        • Guatelli J.
        • Schwartz O.
        • Benichou S.
        J. Virol. 2001; 75: 3971-3976
        • Stevens T.H.
        • Forgac M.
        Annu. Rev. Cell Dev. Biol. 1997; 13: 779-808
        • Nishi T.
        • Forgac M.
        Nat. Rev. Mol. Cell. Biol. 2002; 3: 94-103
        • Mellman I.
        • Fuchs R.
        • Helenius A.
        Annu. Rev. Biochem. 1986; 55: 663-700
        • Ohno H.
        • Stewart J.
        • Fournier M.-C.
        • Bosshart H.
        • Rhee I.
        • Miyatake S.
        • Saito T.
        • Gallusser A.
        • Kirchhausen T.
        • Bonifacino J.S.
        Science. 1995; 269: 1872-1875
        • Klimkait T.
        • Stauffer F.
        • Lupo E.
        • Sonderegger-Rubli C.
        Arch. Virol. 1998; 143: 2109-2131
        • Goldsmith M.A.
        • Warmerdam M.T.
        • Atchison R.E.
        • Miller M.D.
        • Greene W.C.
        J. Virol. 1995; 69: 4112-4121
        • Ho M.N.
        • Hirata R.
        • Umemoto N.
        • Ohya Y.
        • Takatsuki A.
        • Stevens T.H.
        • Anraku Y.
        J. Biol. Chem. 1993; 268: 18286-18292
        • Myers M.
        • Forgac M.
        J. Biol. Chem. 1993; 268: 9184-9186
        • Liu Q.
        • Feng Y.
        • Forgac M.
        J. Biol. Chem. 1994; 269: 31592-31597
        • Zhou Z.
        • Peng S.-B.
        • Crider B.P.
        • Slaughter C.
        • Xie X.-S.
        • Stone D.K.
        J. Biol. Chem. 1998; 273: 5878-5884
        • Xu T.
        • Vasilyeva E.
        • Forgac M.
        J. Biol. Chem. 1999; 274: 28909-28915
        • Schmid S.L.
        Annu. Rev. Biochem. 1997; 66: 511-548
        • Sagermann M.
        • Stevens T.H.
        • Matthews B.W.
        Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 7134-7139
        • Aguilar R.C.
        • Ohno H.
        • Roche K.W.
        • Bonifacino J.S.
        J. Biol. Chem. 1997; 272: 27160-27166
        • Conti E.
        • Izaurralde E.
        Curr. Opin. Cell Biol. 2001; 13: 310-319
        • Bayliss R.
        • Littlewood T.
        • Stewart M.
        Cell. 2000; 102: 99-108
        • Zhou Z.
        • Peng S.B.
        • Crider B.P.
        • Andersen P.
        • Xie X.S.
        • Stone D.K.
        J. Biol. Chem. 1999; 274: 15913-15919
        • Wilkens S.
        • Forgac M.
        J. Biol. Chem. 2001; 276: 44064-44068
        • Domgall I.
        • Venzke D.
        • Luttge U.
        • Ratajczak R.
        • Bottcher B.
        J. Biol. Chem. 2002; 277: 13115-13121
        • Miller M.D.
        • Warmerdam M.T.
        • Page K.A.
        • Feinberg M.A.
        • Greene W.C.
        J. Virol. 1995; 69: 579-584
        • Fackler O.T.
        • d′Aloja P.
        • Baur A.S.
        • Federico M.
        • Peterlin B.M.
        J. Virol. 2001; 75: 6601-6608
        • Zheng Y.
        • Plemenitas A.
        • Linnemann T.
        • Fackler O.T.
        • Peterlin B.M.
        Curr. Biol. 2001; 11: 875-879
        • Fackler O.T.
        • Lu X.
        • Frost J.A.
        • Geyer M.
        • Jiang B.
        • Luo W.
        • Abo A.
        • Alberts A.S.
        • Peterlin B.M.
        Mol. Cell. Biol. 2000; 20: 2619-2627
        • Gross I.
        • Hohenberg H.
        • Wilk T.
        • Wiegers K.
        • Grattinger M.
        • Müller B.
        • Fuller S.
        • Kräusslich H.G.
        EMBO J. 2000; 19: 103-113
        • Franchini G.
        • Mulloy J.C.
        • Koralnik I.J.
        • Lo
        • Monico A.
        • Sparkowski J.J.
        • Andresson T.
        • Goldstein D.J.
        • Schlegel R.
        J. Virol. 1993; 67: 7701-7704
        • Goldstein D.J.
        • Finbow M.E.
        • Andresson T.
        • McLean P.
        • Smith K.
        • Bubb V.
        • Schlegel R.
        Nature. 1991; 352: 347-349
        • Koralnik I.J.
        • Mulloy J.C.
        • Andresson T.
        • Fullen J.
        • Franchini G.
        J. Gen. Virol. 1995; 76: 1909-1916