Abstract
HIV-1 has at its disposal numerous proteins encoded by its genome which provide the required arsenal to establish and maintain infection in its host for a considerable number of years. One of the most important and enigmatic of these proteins is Nef. The Nef protein of HIV-1 plays a fundamental role in the virus life cycle. This small protein of approximately 27 kDa is required for maximal virus replication and disease progression. The mechanisms by which it is able to act as a positive factor during virus replication is an area of intense research and although some controversy surrounds Nef much has been gauged as to how it functions. Its ability to modulate the expression of key cellular receptors important for cell activation and control signal transduction elements and events by interacting with numerous cellular kinases and signalling molecules, including members of the Src family kinases, leading to an effect on host cell function is likely to explain at least in part its role during infection and represents a finely tuned mechanism where this protein assists HIV-1 to control its host.
Similar content being viewed by others
Abbreviations
- Ap:
-
Adapter protein
- CTLs:
-
cytotoxic T-lymphocytes
- IL-2R:
-
IL-2 receptor
- PAK2:
-
p21-activated kinase 2
References
Aiken C, Konner J, Landau N R, Lenburg M E and Trono D 1994 Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain;Cell 76 853–864
Arold S, Franken P, Strub M P, Hoh F, Benichou S, Benarous R and Dumas C 1997 The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling;Structure 5 1361–1372
Arora V K, Molina R P, Foster J L, Blakemore J L, Chernoff J, Fredericksen B L and Garcia J V 2000 Lentivirus Nef specifically activates Pak2;J. Virol. 74 11081–11087
Bandres J C and Ratner L 1994 Human immunodeficiency virus type 1 Nef protein down-regulates transcription factors NF-kappa B and AP-1 in human T-cells in vitro after T-cell receptor stimulation;J. Virol. 68 3243–3249
Baur A S, Sass G, Laffert B, Willbold D, Cheng-Mayer C and Peterlin B M 1997 The N-terminus of Nef from HIV-1/SIV associates with a protein complex containing Lck and a serine kinase;Immunity 6 283–291
Baur A S, Sawai E T, Dazin P, Fantl W J, Cheng-Mayer C and Peterlin B M 1994 HIV-1 Nef leads to inhibition or activation of T-cells depending on its intracellular localization;Immunity 1 373–384
Beaty C D, Franklin T L, Uehara Y and Wilson C B 1994 Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction;Eur. J. Immunol. 24 1278–1284
Bell I, Schaefer T M, Trible R P, Amedee A and Reinhart T A 2001 Down-modulation of the costimulatory molecule, CD28, is a conserved activity of multiple SIV Nefs and is dependent on histidine 196 of Nef;Virology 283 148–158
Benichou S, Liu L X, Erdtmann L, Selig L and Benarous R 1997 Use of the two-hybrid system to identify cellular partners of the HIV1 Nef protein;Res. Virol. 148 71–73
Benson R E, Sanfridson A, Ottinger J S, Doyle C and Cullen B R 1993 Downregulation of cell-surface CD4 expression by simian immunodeficiency virus Nef prevents viral super infection;J. Exp. Med. 177 1561–1566
Bodeus M, Marie-Cardine A, Bougeret C, Ramos-Morales F and Benarous R 1995 In vitro binding and phosphorylation of human immunodeficiency virus type 1 Nef protein by serine/threonine protein kinase;J. Gen. Virol. 76 1337–1344
Bolen J B, Rowley R B, Spana C and Tsygankov A Y 1992 The Src family of tyrosine protein kinases in hemopoietic signal transduction;Faseb J. 6 3403–3409
Brady H J, Pennington D J, Miles C G and Dzierzak E A 1993 CD4 cell surface downregulation in HIV-1 Nef transgenic mice is a consequence of intracellular sequestration;EMBO J. 12 4923–4932
Briggs S D, Scholtz B, Jacque J M, Swingler S, Stevenson M and Smithgall T E 2001 HIV-1 Nef promotes survival of myeloid cells by a Stat3-dependent pathway;J. Biol. Chem. 276 25605–25611
Briggs S D, Sharkey M, Stevenson M and Smithgall TE 1997 SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1;J. Biol. Chem. 272 17899–17902
Brown A, Wang X, Sawai E and Cheng-Mayer C 1999 Activation of the PAK-related kinase by human immunodeficiency virus type 1 Nef in primary human peripheral blood lymphocytes and macrophages leads to phosphorylation of a PIX-p95 complex;J. Virol. 73 9899–9907
Campbell S M, Crowe S M and Mak J 2001 Lipid rafts and HIV-1: from viral entry to assembly of progeny virions;J. Clin. Virol. 22 217–227
Chang A H, O’Shaughnessy M V and Jirik F R 2001 Hck SH3 domain-dependent abrogation of Nef-induced class 1 MHC down-regulation;Eur. J. Immunol. 31 2382–2387
Chen B K, Gandhi R T and Baltimore D 1996 CD4 downmodulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef;J. Virol. 70 6044–6053
Cheng H, Hoxie J P and Parks W P 1999 The conserved core of human immunodeficiency virus type 1 Nef is essential for association with Lck and for enhanced viral replication in T-lymphocytes;Virology 264 5–15
Coates K, Cooke S J, Mann D A and Harris M P G 1997 Protein kinase C-mediated phosphorylation of HIV-I nef in human cell lines;J. Biol. Chem. 272 12289–12294
Collette Y, Arold S, Picard C, Janvier K, Benichou S, Benarous R, Olive D and Dumas C 2000 HIV-2 and SIV nef proteins target different Src family SH3 domains than does HIV-1 Nef because of a triple amino acid substitution;J. Biol. Chem. 275 4171–4176
Collette Y, Dutartre H, Benziane A, Ramos M, Benarous R, Harris M and Olive D 1996 Physical and functional interaction of Nef with Lck. HIV-1 Nef-induced T-cell signaling defects;J. Biol. Chem. 271 6333–6341
Collette Y and Olive D 1999 The primate lentivirus-encoded Nef protein can regulate several steps of the viral replication cycle;Virology 265 173–177
Collins K L, Chen B K, Kalams S A, Walker B D and Baltimore D 1998 HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes;Nature (London) 391 397–401
Craig H M, Pandori M W and Guatelli J C 1998 Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity;Proc. Natl. Acad. Sci. USA 95 11229–11234
Crise B and Rose J K 1992 Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulum;J. Virol. 66 2296–2301
De S K and Marsh J W 1994 HIV-1 Nef inhibits a common activation pathway in NIH-3T3 cells;J. Biol. Chem. 269 6656–6660
De S K, Venkateshan C N, Seth P, Gajdusek D C and Gibbs C J 1998 Adenovirus-mediated human immunodeficiency virus-1 Nef expression in human monocytes/macrophages and effect of Nef on downmodulation of Fcgamma receptors and expression of monokines;Blood 91 2108–2117
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, Larison V A, Crowe S, Maerz A, Sonza S, Learmont J, Sullivan J S, Cunningham A, Dwyer D, Dowton D and Mills J 1995 Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients [see comments];Science 270 988–991
Dutartre H, Harris M, Olive D and Collette Y 1998 The human immunodeficiency virus type 1 Nef protein binds the Src-related tyrosine kinase Lck SH2 domain through a novel phosphotyrosine independent mechanism;Virology 247 200–211
Ernst C A, Zhang Y J, Hancock P R, Rutledge B J, Corless C L and Rollins B J 1994 Biochemical and biologic characterization of murine monocyte chemoattractant protein-1. Identification of two functional domains;J. Immunol. 152 3541–3549
Fackler O T, Luo W, Geyer M, Alberts A S and Peterlin B M 1999 Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions;Mol. Cell 3 729–739
Fauci A S 1988 The human immunodeficiency virus: infectivity and mechanisms of pathogenesis;Science 239 617–622
Flaherty M T, Barber S A and Clements J E 1998 Neurovirulent simian immunodeficiency virus incorporates a Nef-associated kinase activity into virions;AIDS Res. Hum. Retroviruses 14 163–170
Frank S J, Samelson L E and Klausner R D 1990 The structure and signalling functions of the invariant T cell receptor components;Semin. Immunol. 2 89–97
Garcia J V, Alfano J and Miller A D 1993 The negative effect of human immunodeficiency virus type 1 Nef on cell surface CD4 expression is not species specific and requires the cytoplasmic domain of CD4;J. Virol. 67 1511–1516
Garcia J V and Miller A D 1991 Serine phosphorylation-independent downregulation of cell-surface CD4 by nef;Nature (London) 350 508–511
Geleziunas R, Xu W, Takeda K, Ichijo H and Greene W C 2001 HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell;Nature (London) 410 834–838
Gratton S, Yao X J, Venkatesan S, Cohen E A and Sekaly R P 1996 Molecular analysis of the cytoplasmic domain of CD4: overlapping but noncompetitive requirement for lck association and down-regulation by Nef;J. Immunol. 157 3305–3311
Greenberg M, DeTulleo L, Rapoport I, Skowronski J and Kirchhausen T 1998 A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4;Curr. Biol. 8 1239–1242
Greenberg M E, Bronson S, Lock M, Neumann M, Pavlakis G N and Skowronski J 1997 Co-localization of HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nefinduced CD4 down-regulation;EMBO J. 16 6964–6976
Greenway A, Azad A and McPhee D 1995 Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines;J. Virol. 69 1842–1850
Greenway A, Azad A, Mills J and McPhee D 1996 Human immunodeficiency virus type 1 Nef binds directly to Lck and mitogen-activated protein kinase, inhibiting kinase activity;J. Virol. 70 6701–6708
Greenway A L, Dutartre H, Allen K, McPhee D A, Olive D and Collette Y 1999 Simian immunodeficiency virus and human immunodeficiency virus type 1 nef proteins show distinct patterns and mechanisms of Src kinase activation;J. Virol. 73 6152–6158
Greenway A L, McPhee D A, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S and Lambert P 2002 Human immunodeficiency virus type 1 Nef binds to tumour suppressor p53 and protects cells against p53-mediated apoptosis;J. Virol. 76 2692–2702
Greenway A L, McPhee D A, Grgacic E, Hewish D, Lucantoni A, Macreadie I and Azad A 1994 Nef 27, but not the Nef 25 isoform of human immunodeficiency virus-type 1 pNL4.3 down-regulates surface CD4 and IL-2R expression in peripheral blood mononuclear cells and transformed T cells;Virology 198 245–256
Grzesiek S, Stahl S J, Wingfield P T and Bax A 1996 The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR;Biochemistry 35 10256–10261
Gupta D, Jin Y P and Dziarski R 1995 Peptidoglycan induces transcription and secretion of TNF-alpha and activation of lyn, extracellular signal-regulated kinase, and rsk signal transduction proteins in mouse macrophages;J. Immunol. 155 2620–2630
Hanna Z, Kay D G, Rebai N, Guimond A, Jothy S and Jolicoeur P 1998 Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice;Cell 95 163–175
Hanna Z, Weng X, Kay D G, Poudrier J, Lowell C and Jolicoeur P 2001 The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck;J. Virol. 75 9378–9392
Harris M P and Neil J C 1994 Myristoylation-dependent binding of HIV-1 Nef to CD4;J. Mol. Biol. 241 136–142
Holly S P and Blumer K J 1999 PAK-family kinases regulate cell and actin polarization throughout the cell cycle ofSaccharomyces cerevisiae;J. Cell. Biol. 147 845–856
Holstein S E, Drucker M and Robinson D G 1994 Identification of a beta-type adaptin in plant clathrin-coated vesicles;J. Cell. Sci. 107 945–953
Horak I D, Gress R E, Lucas P J, Horak E M, Waldmann T A and Bolen J B 1991 T-lymphocyte interleukin 2-dependent tyrosine protein kinase signal transduction involves the activation of p56lck;Proc. Natl. Acad. Sci. USA 88 1996–2000
Iafrate A J, Bronson S and Skowronski J 1997 Separable functions of Nef disrupt two aspects of T cell receptor machinery: CD4 expression and CD3 signaling;EMBO J. 16 673–684
Jacque J M, Mann A, Enslen H, Sharova N, Brichacek B, Davis R J and Stevenson M 1998 Modulation of HIV-1 infectivity by MAPK, a virion-associated kinase;EMBO J. 17 2607–2618
Jakobi R, Moertl E and Koeppel M A 2001 p21-activated protein kinase gamma-PAK suppresses programmed cell death of BALB3T3 fibroblasts;J. Biol. Chem. 276 16624–16634
Kamp W, Berk M B, Visser C J and Nottet H S 2000 Mechanisms of HIV-1 to escape from the host immune surveillance;Eur. J. Clin. Invest. 30 740–746
Kestler H W D, Ringler D J, Mori K, Panicali D L, Sehgal P K, Daniel M D and Desrosiers R C 1991 Importance of the nef gene for maintenance of high virus loads and for development of AIDS;Cell 65 651–662
Kirchhoff F, Greenough T C, Brettler D B, Sullivan J L and Desrosiers R C 1995 Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection [see comments];N. Engl. J. Med. 332 228–232
Le Gall S, Erdtmann L, Benichou S, Berlioz-Torrent C, Liu L, Benarous R, Heard J M and Schwartz O 1998 Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules;Immunity 8 483–495
Le Gall S, Heard J M and Schwartz O 1997 Analysis of Nefinduced MHC-I endocytosis;Res. Virol. 148 43–47
Lee C H, Leung B, Lemmon M A, Zheng J, Cowburn D, Kuriyan J and Saksela K 1995 A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein;EMBO J. 14 5006–5015
Lee C H, Saksela K, Mirza U A, Chait B T and Kuriyan J 1996 Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain;Cell 85 931–942
Letourneur F and Klausner R D 1992 A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains;Cell 69 1143–1157
Lock M, Greenberg M E, Iafrate A J, Swigut T, Muench J, Kirchhoff F, Shohdy N and Skowronski J 1999 Two elements target SIV Nef to the AP-2 clathrin adaptor complex, but only one is required for the induction of CD4 endocytosis;EMBO J. 18 2722–2733
Luria S, Chambers I and Berg P 1991 Expression of the type 1 human immunodeficiency virus Nef protein in T-cells prevents antigen receptor-mediated induction of interleukin 2 mRNA;Proc. Natl. Acad. Sci. USA 88 5326–5330
Mangasarian A, Foti M, Aiken C, Chin D, Carpentier J L and Trono D 1997 The HIV-1 Nef protein acts as a connector with sorting pathways in the Golgi and at the plasma membrane;Immunity 6 67–77
Mangasarian A, Piguet V, Wang J K, Chen Y L and Trono D 1999 Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking;J. Virol. 73 1964–1973
Manninen A, Hiipakka M, Vihinen M, Lu W, Mayer B J and Saksela K 1998 SH3-Domain binding function of HIV-1 Nef is required for association with a PAK-related kinase;Virology 250 273–282
Manninen A, Renkema G H and Saksela K 2000 Synergistic activation of NFAT by HIV-1 nef and the Ras/MAPK pathway;J. Biol. Chem. 275 16513–16517
Mariani R and Skowronski J 1993 CD4 down-regulation by nef alleles isolated from human immunodeficiency virus type 1-infected individuals;Proc. Natl. Acad. Sci. USA 90 5549–5553
Miller M D, Warmerdam M T, Gaston I, Greene W C and Feinberg M B 1994 The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages;J. Exp. Med. 179 101–113
Minami Y, Kono T, Yamada K, Kobayashi N, Kawahara A, Perlmutter R M and Taniguchi T 1993 Association of p56lck with IL-2 receptor beta chain is critical for the IL-2-induced activation of p56lck;EMBO J. 12 759–768
Moarefi I, LaFevre-Bernt M, Sicheri F, Huse M, Lee C H, Kuriyan J and Miller W T 1997 Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement [see comments];Nature (London) 385 650–653
Mountz J D, Zhou T, Wu J, Wang W, Su X and Cheng J 1995 Regulation of apoptosis in immune cells;J. Clin. Immunol. 15 1–16
Niederman T M, Hastings W R, Luria S, Bandres J C and Ratner L 1993 HIV-1 Nef protein inhibits the recruitment of AP-1 DNA-binding activity in human T-cells;Virology 194 338–344
Nunn M F and Marsh J W 1996 Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family;J. Virol. 70 6157–6161
Ono A and Freed E O 2001 Plasma membrane rafts play a critical role in HIV-1 assembly and release;Proc. Natl. Acad. Sci. USA 98 13925–13930
Oyaizu N, Than S, McCloskey T W and Pahwa S 1995 Requirement of p56lck in T-cell receptor/CD3-mediated apoptosis and Fas-ligand induction in Jurkat cells;Biochem. Biophys. Res. Commun. 213 994–1001
Pandori M, Craig H, Moutouh L, Corbeil J and Guatelli J 1998 Virological importance of the protease-cleavage site in human immunodeficiency virus type 1: Nef is independent of both intravirion processing and CD4 down-regulation;Virology 251 302–316
Pandori M W, Fitch N J, Craig H M, Richman D D, Spina C A and Guatelli J C 1996 Producer-cell modification of human immunodeficiency virus type 1: Nef is a virion protein;J. Virol. 70 4283–4290
Piguet V, Chen Y L, Mangasarian A, Foti M, Carpentier J L and Trono D 1998 Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the mu chain of adaptor complexes;EMBO J. 17 2472–2481
Piguet V, Gu F, Foti M, Demaurex N, Gruenberg J, Carpentier J L and Trono D 1999a Nef-induced CD4 degradation: a diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of beta-COP in endosomes;Cell 97 63–73
Piguet V, Schwartz O, Le Gall S and Trono D 1999b The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors;Immunol. Rev. 168 51–63
Piguet V and Trono D 1999 The Nef protein of primate lentiviruses;Rev. Med. Virol. 9 111–120
Renkema G H, Manninen A and Saksela K 2001 Human immunodeficiency virus type 1 Nef selectively associates with a catalytically active subpopulation of p21-activated kinase 2 (PAK2) independently of PAK2 binding to Nck or beta-PIX;J. Virol. 75 2154–2160
Rhee S S and Marsh J W 1994 HIV-1 Nef activity in murine T-cells. CD4 modulation and positive enhancement;J. Immunol. 152 5128–5134
Riggs N L, Craig H M, Pandori M W and Guatelli J C 1999 The dileucine-based sorting motif in HIV-1 Nef is not required for down-regulation of class I MHC;Virology 258 203–207
Rousso I, Mixon M B, Chen B K and Kim P S 2000 Palmitoylation of the HIV-1 envelope glycoprotein is critical for viral infectivity;Proc. Natl. Acad. Sci. USA 97 13523–13525
Rudd C E, Trevillyan J M, Dasgupta J D, Wong L L and Schlossman S F 1988 The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp 58) from human T lymphocytes;Proc. Natl. Acad. Sci. USA 85 5190–5194
Saksela K, Cheng G and Baltimore D 1995 Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4;EMBO J. 14 484–491
Salghetti S, Mariani R and Skowronski J 1995 Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail;Proc. Natl. Acad. Sci. USA 92 349–353
Sawai E T, Baur A S, Peterlin B M, Levy J A and Cheng-Mayer C 1995 A conserved domain and membrane targeting of Nef from HIV and SIV are required for association with a cellular serine kinase activity;J. Biol. Chem. 270 15307–15314
Sawai E T, Baur A, Struble H, Peterlin B M, Levy J A and Cheng-Mayer C 1994 Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes;Proc. Natl. Acad. Sci. USA 91 1539–1543
Sawai E T, Khan I H, Montbriand P M, Peterlin B M, Cheng-Mayer C and Luciw P A 1996 Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques;Curr. Biol. 6 1519–1527
Schrager J A and Marsh J W 1999 HIV-1 Nef increases T-cell activation in a stimulus-dependent manner;Proc. Natl. Acad. Sci. USA 96 8167–8172
Schwartz O, Marechal V, Danos O and Heard J M 1995 Human immunodeficiency virus type 1 Nef increases the efficiency of reverse transcription in the infected cell;J. Virol. 69 4053–4059
Schwartz O, Marechal V, Le Gall S, Lemonnier F and Heard J M 1996 Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein;Nat. Med. 2 338–342
Simard M C, Chrobak P, Kay D G, Hanna Z, Jothy S and Jolicoeur P 2002 Expression of simian immunodeficiency virus nef in immune cells of transgenic mice leads to a severe AIDS-like disease;J. Virol. 76 3981–3995
Simmons A, Aluvihare V and McMichael A 2001 Nef triggers a transcriptional program in T-cells imitating singlesignal T cell activation and inducing HIV virulence mediators;Immunity 14 763–777
Skowronski J, Parks D and Mariani R 1993 Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene;EMBO J. 12 703–713
Smith B L, Krushelnycky B W, Mochly-Rosen D and Berg P 1996 The HIV nef protein associates with protein kinase C theta;J. Biol. Chem. 271 16753–16757
Swigut T, Shohdy N and Skowronski J 2001 Mechanism for down-regulation of CD28 by Nef;EMBO J. 20 1593–1604
Swingler S, Mann A, Jacque J, Brichacek B, Sasseville V G, Williams K, Lackner A A, Janoff E N, Wang R, Fisher D and Stevenson M 1999 HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages;Nat. Med. 5 997–1103
Van Parijs L, Peterson D A and Abbas A K 1998 The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens;Immunity 8 265–274
Veillette A, Horak I D, Horak E M, Bookman M A and Bolen J B 1988 Alterations of the lymphocyte-specific protein tyrosine kinase (p56lck) during T-cell activation;Mol. Cell. Biol. 8 4353–4361
Weiss A 1993 T cell antigen receptor signal transduction: a tale of tails and cytoplasmic protein-tyrosine kinases;Cell 73 209–212
Weiss A and Littman D R 1994 Signal transduction by lymphocyte antigen receptors;Cell 76 263–274
Weiss A, Wiskocil R L and Stobo J D 1984 The role of T3 surface molecules in the activation of human T cells: a twostimulus requirement for IL 2 production reflects events occurring at a pre-translational level;J. Immunol. 133 123–128
Willey R L, Maldarelli F, Martin M A and Strebel K 1992 Human immunodeficiency virus type 1 Vpu protein regulates the formation of intracellular gp160-CD4 complexes;J. Virol. 66 226–234
Wiskerchen M and Cheng-Mayer C 1996 HIV-1 Nef association with cellular serine kinase correlates with enhanced virion infectivity and efficient proviral DNA synthesis;Virology 224 292–301
Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d’Aloja P, Schurmann A and Baur A S 2001 HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals;Nat. Med. 7 1217–1224
Xu X N, Laffert B, Screaton G R, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael A J and Baur A S 1999 Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain;J. Exp. Med. 189 1489–1496
Yoon K, Jeong J G and Kim S 2001 Stable expression of human immunodeficiency virus type 1 Nef confers resistance against Fas-mediated apoptosis;AIDS Res. Hum. Retroviruses 17 99–104
Zang M, Waelde C A, Xiang X, Rana A, Wen R and Luo Z 2001 Microtubule integrity regulates Pak leading to Rasindependent activation of Raf-1. Insights into mechanisms of Raf-1 activation;J. Biol. Chem. 276 25157–25165
Zhou J and Aiken C 2001 Nef enhances human immunodeficiency virus type 1 infectivity resulting from intervirion fusion: evidence supporting a role for Nef at the virion envelope;J. Virol. 75 5851–5859
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Greenway, A.L., Holloway, G., McPhee, D.A. et al. HIV-1 Nef control of cell signalling molecules: Multiple strategies to promote virus replication. J. Biosci. 28, 323–335 (2003). https://doi.org/10.1007/BF02970151
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF02970151