nef gene products


Summary: Products of the retroviral NEF GENE. They play a role as accessory proteins that influence the rate of viral infectivity and the destruction of the host immune system. nef gene products were originally found as factors that trans-suppress viral replication and function as negative regulators of transcription. nef stands for negative factor.

Top Publications

  1. Matthews P, Prendergast A, Leslie A, Crawford H, Payne R, Rousseau C, et al. Central role of reverting mutations in HLA associations with human immunodeficiency virus set point. J Virol. 2008;82:8548-59 pubmed publisher
    ..The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses. ..
  2. Brisibe E, Okada N, Mizukami H, Okuyama H, Fujii Y. RNA interference: potentials for the prevention of HIV infections and the challenges ahead. Trends Biotechnol. 2003;21:306-11 pubmed
  3. Schaefer T, Bell I, Pfeifer M, Ghosh M, Trible R, Fuller C, et al. The conserved process of TCR/CD3 complex down-modulation by SIV Nef is mediated by the central core, not endocytic motifs. Virology. 2002;302:106-22 pubmed
  4. Yang O, Nguyen P, Kalams S, Dorfman T, Gottlinger H, Stewart S, et al. Nef-mediated resistance of human immunodeficiency virus type 1 to antiviral cytotoxic T lymphocytes. J Virol. 2002;76:1626-31 pubmed
    ..We conclude that Nef (and not Vpr) contributes to functional HIV-1 immune evasion and that this effect is mediated by diminished antigen presentation to CTL. ..
  5. Kirchhoff F, Schindler M, Specht A, Arhel N, Munch J. Role of Nef in primate lentiviral immunopathogenesis. Cell Mol Life Sci. 2008;65:2621-36 pubmed publisher
    ..This evolutionary loss of a specific Nef function may contribute to the high virulence of HIV-1 in humans. ..
  6. Brenner M, Munch J, Schindler M, Wildum S, Stolte N, Stahl Hennig C, et al. Importance of the N-distal AP-2 binding element in Nef for simian immunodeficiency virus replication and pathogenicity in rhesus macaques. J Virol. 2006;80:4469-81 pubmed
    ..Our results imply that both the Nef functions that were disrupted by the delta64-67 mutation and the activities that remained intact contribute to viral pathogenicity. ..
  7. Agopian K, Wei B, Garcia J, Gabuzda D. A hydrophobic binding surface on the human immunodeficiency virus type 1 Nef core is critical for association with p21-activated kinase 2. J Virol. 2006;80:3050-61 pubmed
    ..This binding surface includes exposed and recessed hydrophobic residues and may participate in an as-yet-unidentified protein-protein interaction to facilitate Pak2 activation. ..
  8. Coleman S, Madrid R, Van Damme N, Mitchell R, Bouchet J, Servant C, et al. Modulation of cellular protein trafficking by human immunodeficiency virus type 1 Nef: role of the acidic residue in the ExxxLL motif. J Virol. 2006;80:1837-49 pubmed
    ..The data suggest that the E160 residue plays a differential role in the modulation of leucine-dependent Nef-targets and support a model in which distinct AP complexes are used by Nef to modulate different cellular proteins. ..
  9. Coleman S, Van Damme N, Day J, Noviello C, Hitchin D, Madrid R, et al. Leucine-specific, functional interactions between human immunodeficiency virus type 1 Nef and adaptor protein complexes. J Virol. 2005;79:2066-78 pubmed
    ..This binding likely underlies the unusual ability of Nef to induce the stabilization of these complexes on endosomal membranes, an activity that correlates with enhancement of viral replication. ..

More Information


  1. Omoto S, Ito M, Tsutsumi Y, Ichikawa Y, Okuyama H, Brisibe E, et al. HIV-1 nef suppression by virally encoded microRNA. Retrovirology. 2004;1:44 pubmed
    ..These data suggest that nef/U3 miRNAs produced in HIV-1-infected cells may suppress both Nef function and HIV-1 virulence through the RNAi pathway. ..
  2. Cavrois M, Neidleman J, Yonemoto W, Fenard D, Greene W. HIV-1 virion fusion assay: uncoating not required and no effect of Nef on fusion. Virology. 2004;328:36-44 pubmed
  3. Stumptner Cuvelette P, Jouve M, Helft J, Dugast M, Glouzman A, Jooss K, et al. Human immunodeficiency virus-1 Nef expression induces intracellular accumulation of multivesicular bodies and major histocompatibility complex class II complexes: potential role of phosphatidylinositol 3-kinase. Mol Biol Cell. 2003;14:4857-70 pubmed
    ..Given that human immunodeficiency virus recruits the MVB machinery for its assembly process, our data raise the possibility that Nef is involved in viral assembly through its effect on MVBs. ..
  4. Blagoveshchenskaya A, Thomas L, Feliciangeli S, Hung C, Thomas G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell. 2002;111:853-66 pubmed
    ..These data provide new insights into the cellular basis of HIV-1 immunoevasion. ..
  5. van Baalen C, Guillon C, van Baalen M, Verschuren E, Boers P, Osterhaus A, et al. Impact of antigen expression kinetics on the effectiveness of HIV-specific cytotoxic T lymphocytes. Eur J Immunol. 2002;32:2644-52 pubmed
    ..This provides rationale for immunization strategies that aim at inducing, boosting or skewing CTL responses to early regulatory proteins in AIDS vaccine development. ..
  6. Churchill M, Rhodes D, Learmont J, Sullivan J, Wesselingh S, Cooke I, et al. Longitudinal analysis of human immunodeficiency virus type 1 nef/long terminal repeat sequences in a cohort of long-term survivors infected from a single source. J Virol. 2006;80:1047-52 pubmed
    ..The in vivo pathogenicity of attenuated HIV-1 is therefore dictated by viral and/or host factors other than those that impose a unidirectional selection pressure on the nef/LTR region of the HIV-1 genome. ..
  7. Janvier K, Kato Y, Boehm M, Rose J, Martina J, Kim B, et al. Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma1 and AP-3 delta-sigma3 hemicomplexes. J Cell Biol. 2003;163:1281-90 pubmed
    ..These observations reveal a novel mode of recognition of sorting signals involving the gamma/delta and sigma subunits of AP-1 and AP-3. ..
  8. Peng B, Voltan R, Cristillo A, Alvord W, Davis Warren A, Zhou Q, et al. Replicating Ad-recombinants encoding non-myristoylated rather than wild-type HIV Nef elicit enhanced cellular immunity. AIDS. 2006;20:2149-57 pubmed
    ..The results support the hypothesis that immunization with Ad-recombinants encoding HIVnefNM rather than HIVnefWT elicits enhanced cellular immunity resulting from improved antigen presentation and greater T-cell help. ..
  9. Fischer W, Perkins S, Theiler J, Bhattacharya T, Yusim K, Funkhouser R, et al. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med. 2007;13:100-6 pubmed
  10. Sol Foulon N, Moris A, Nobile C, Boccaccio C, Engering A, Abastado J, et al. HIV-1 Nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. Immunity. 2002;16:145-55 pubmed
    ..These results provide new insights into how HIV-1 spreads from DCs to T lymphocytes and manipulates immune responses. They help explain how Nef may act as a virulence factor in vivo. ..
  11. Vogel T, Friedrich T, O Connor D, Rehrauer W, Dodds E, Hickman H, et al. Escape in one of two cytotoxic T-lymphocyte epitopes bound by a high-frequency major histocompatibility complex class I molecule, Mamu-A*02: a paradigm for virus evolution and persistence?. J Virol. 2002;76:11623-36 pubmed
    ..Differential selection by CTL may therefore be a paradigm of immunodeficiency virus infection. ..
  12. Schindler M, Munch J, Kutsch O, Li H, Santiago M, Bibollet Ruche F, et al. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell. 2006;125:1055-67 pubmed
    ..This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans...
  13. Churchill M, Sterjovski J, Gray L, Cowley D, Chatfield C, Learmont J, et al. Longitudinal analysis of nef/long terminal repeat-deleted HIV-1 in blood and cerebrospinal fluid of a long-term survivor who developed HIV-associated dementia. J Infect Dis. 2004;190:2181-6 pubmed
    ..Thus, nef/LTR-deleted HIV-1 strains may undergo compartmentalized evolution in long-term survivors and cause neurologic disease. ..
  14. Costa L, Chen N, Lopes A, Aguiar R, Tanuri A, Plemenitas A, et al. Interactions between Nef and AIP1 proliferate multivesicular bodies and facilitate egress of HIV-1. Retrovirology. 2006;3:33 pubmed
    ..We conclude that by binding GagPol and AIP1, Nef not only proliferates MVBs but also contributes to the egress of viral particles from infected cells. ..
  15. Schindler M, Würfl S, Benaroch P, Greenough T, Daniels R, Easterbrook P, et al. Down-modulation of mature major histocompatibility complex class II and up-regulation of invariant chain cell surface expression are well-conserved functions of human and simian immunodeficiency virus nef alleles. J Virol. 2003;77:10548-56 pubmed
    ..Overall, our results suggest that the ability of Nef to interfere with MHC-II antigen presentation might play a role in AIDS pathogenesis. ..
  16. Jekle A, Schramm B, Jayakumar P, Trautner V, Schols D, De Clercq E, et al. Coreceptor phenotype of natural human immunodeficiency virus with nef deleted evolves in vivo, leading to increased virulence. J Virol. 2002;76:6966-73 pubmed
    ..In conclusion, these data show that an in vivo evolution of the tropism of this nef-deleted strain toward an X4 phenotype was associated with a higher cytopathic potential and progression to AIDS. ..
  17. Kiepiela P, Leslie A, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature. 2004;432:769-75 pubmed
    ..The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design. ..
  18. Sandrin V, Cosset F. Intracellular versus cell surface assembly of retroviral pseudotypes is determined by the cellular localization of the viral glycoprotein, its capacity to interact with Gag, and the expression of the Nef protein. J Biol Chem. 2006;281:528-42 pubmed
    ..Finally, the expression of Nef proteins specifically enhanced the incorporation of the retroviral GPs by increasing their localization in late endosomes. ..
  19. Williams M, Roeth J, Kasper M, Fleis R, Przybycin C, Collins K. Direct binding of human immunodeficiency virus type 1 Nef to the major histocompatibility complex class I (MHC-I) cytoplasmic tail disrupts MHC-I trafficking. J Virol. 2002;76:12173-84 pubmed
    ..In addition, they provide the first direct evidence indicating that Nef functions as an adaptor molecule able to link MHC-I to cellular trafficking proteins. ..
  20. Geyer M, Fackler O, Peterlin B. Subunit H of the V-ATPase involved in endocytosis shows homology to beta-adaptins. Mol Biol Cell. 2002;13:2045-56 pubmed
    ..Based on recent structural analysis, our results suggest that the di-leucine-binding domain consists of a HEAT or ARM repeat protein fold. ..
  21. Geyer M, Yu H, Mandic R, Linnemann T, Zheng Y, Fackler O, et al. Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex 2 and connects Nef to the endocytic machinery. J Biol Chem. 2002;277:28521-9 pubmed
    ..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. ..
  22. Currier J, Dowling W, Wasunna K, Alam U, Mason C, Robb M, et al. Detection of high frequencies of HIV-1 cross-subtype reactive CD8 T lymphocytes in the peripheral blood of HIV-1-infected Kenyans. AIDS. 2003;17:2149-57 pubmed
    ..Autologous B-lymphoblastoid cell lines infected with recombinant vaccinia-viruses expressing gag, env and nef gene products from HIV-1 subtypes A-H were used as antigen-presenting cells to stimulate CD8 T cells from cryopreserved ..
  23. Haller C, Rauch S, Michel N, Hannemann S, Lehmann M, Keppler O, et al. The HIV-1 pathogenicity factor Nef interferes with maturation of stimulatory T-lymphocyte contacts by modulation of N-Wasp activity. J Biol Chem. 2006;281:19618-30 pubmed
    ..Together, our results demonstrate that Nef alters both the amount and composition of signaling microclusters. We propose modulation of actin dynamics as an important mechanism for Nef-induced alterations of TCR signaling. ..
  24. Lucchiari Hartz M, Lindo V, Hitziger N, Gaedicke S, Saveanu L, van Endert P, et al. Differential proteasomal processing of hydrophobic and hydrophilic protein regions: contribution to cytotoxic T lymphocyte epitope clustering in HIV-1-Nef. Proc Natl Acad Sci U S A. 2003;100:7755-60 pubmed
    ..The results suggest that differential proteasomal processing contributes importantly to the clustering of CTL epitopes in hydrophobic regions. ..
  25. Manninen A, Saksela K. HIV-1 Nef interacts with inositol trisphosphate receptor to activate calcium signaling in T cells. J Exp Med. 2002;195:1023-32 pubmed
  26. Barugahare B, Baker C, K Aluoch O, Donovan R, Elrefaei M, Eggena M, et al. Human immunodeficiency virus-specific responses in adult Ugandans: patterns of cross-clade recognition. J Virol. 2005;79:4132-9 pubmed
    ..High sequence homologies were also observed between consensus peptides and sequences from viral isolates, supporting the use of consensus amino acid sequences to identify immunogenic regions in studies of large populations. ..
  27. Roeth J, Collins K. Human immunodeficiency virus type 1 Nef: adapting to intracellular trafficking pathways. Microbiol Mol Biol Rev. 2006;70:548-63 pubmed
  28. Dave R, Pomerantz R. Antiviral effects of human immunodeficiency virus type 1-specific small interfering RNAs against targets conserved in select neurotropic viral strains. J Virol. 2004;78:13687-96 pubmed
  29. Michel N, Ganter K, Venzke S, Bitzegeio J, Fackler O, Keppler O. The Nef protein of human immunodeficiency virus is a broad-spectrum modulator of chemokine receptor cell surface levels that acts independently of classical motifs for receptor endocytosis and Galphai signaling. Mol Biol Cell. 2006;17:3578-90 pubmed
    ..Nef uses a mechanism that is distinct from well-established pathways orchestrating CKR metabolism and offers an interesting tool to study the multifaceted biology of CKRs. ..
  30. Betts M, Ambrozak D, Douek D, Bonhoeffer S, Brenchley J, Casazza J, et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol. 2001;75:11983-91 pubmed
    ..These results suggest that overall frequencies of HIV-specific T cells are not the sole determinant of immune-mediated protection in HIV-infection. ..
  31. Varin A, Manna S, Quivy V, Decrion A, Van Lint C, Herbein G, et al. Exogenous Nef protein activates NF-kappa B, AP-1, and c-Jun N-terminal kinase and stimulates HIV transcription in promonocytic cells. Role in AIDS pathogenesis. J Biol Chem. 2003;278:2219-27 pubmed
    ..Therefore, our results suggest that exogenous Nef could fuel the progression of the disease via stimulation of HIV-1 provirus present in such cellular reservoirs as mononuclear phagocytes in HIV-infected patients. ..
  32. Otake K, Omoto S, Yamamoto T, Okuyama H, Okada H, Okada N, et al. HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors. AIDS. 2004;18:189-98 pubmed
    ..Nef may be involved in both viral replication and the wasting syndrome associated with AIDS. ..
  33. Michel N, Allespach I, Venzke S, Fackler O, Keppler O. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4. Curr Biol. 2005;15:714-23 pubmed
    ..This evasion strategy likely represents a mechanism by which the pathogenicity factor Nef elevates viral replication in vivo and thus promotes AIDS pathogenesis. ..
  34. Keppler O, Tibroni N, Venzke S, Rauch S, Fackler O. Modulation of specific surface receptors and activation sensitization in primary resting CD4+ T lymphocytes by the Nef protein of HIV-1. J Leukoc Biol. 2006;79:616-27 pubmed
    ..Our data support the involvement of modulation of a defined set of cell surface receptors and sensitization to activation rather than an autonomous activation function in the role of Nef in HIV-1 pathogenesis. ..
  35. Janvier K, Craig H, Hitchin D, Madrid R, Sol Foulon N, Renault L, et al. HIV-1 Nef stabilizes the association of adaptor protein complexes with membranes. J Biol Chem. 2003;278:8725-32 pubmed
    ..The stabilization of these complexes on membranes may underlie the pleiotropic effects of Nef on protein trafficking within the endosomal system. ..
  36. Tobiume M, Takahoko M, Yamada T, Tatsumi M, Iwamoto A, Matsuda M. Inefficient enhancement of viral infectivity and CD4 downregulation by human immunodeficiency virus type 1 Nef from Japanese long-term nonprogressors. J Virol. 2002;76:5959-65 pubmed
    ..It awaits further study to conclude that these characteristics of nef alleles are the cause or the consequence of the long-term nonprogression after HIV-1 infection. ..
  37. Krautkrämer E, Giese S, Gasteier J, Muranyi W, Fackler O. Human immunodeficiency virus type 1 Nef activates p21-activated kinase via recruitment into lipid rafts. J Virol. 2004;78:4085-97 pubmed
    ..Together, these data suggest that Nef induces signal transduction via the recruitment of a signaling machinery including Pak into lipid rafts, thereby mimicking a physiological cellular mechanism to initiate the TCR cascade. ..
  38. Das A, Brummelkamp T, Westerhout E, Vink M, Madiredjo M, Bernards R, et al. Human immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition. J Virol. 2004;78:2601-5 pubmed
    ..However, as is known for antiviral drug therapy against HIV-1, antiviral approaches involving RNAi should be used in a combined fashion to prevent the emergence of resistant viruses. ..
  39. Roeth J, Williams M, Kasper M, Filzen T, Collins K. HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail. J Cell Biol. 2004;167:903-13 pubmed
    ..In sum, our evidence suggests that binding of AP-1 to the Nef-MHC-I complex is an important step required for inhibition of antigen presentation by HIV. ..
  40. Witte V, Laffert B, Rosorius O, Lischka P, Blume K, Galler G, et al. HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane. Mol Cell. 2004;13:179-90 pubmed
    ..Our results suggest a link between membrane-associated activation processes and transcriptional derepression and demonstrate how HIV exploits this mechanism...
  41. Chakraborty R, Gillespie G, Reinis M, Rostron T, Dong T, Philpott S, et al. HIV-1-specific CD8 T cell responses in a pediatric slow progressor infected as a premature neonate. AIDS. 2002;16:2085-7 pubmed
    ..HIV-1 infection as early as 25 weeks' gestation may thus results in the development of immune responses that control viral replication and lead to prolonged survival. ..
  42. Fournier C, Cortay J, Carbonnelle C, Ehresmann C, Marquet R, Boulanger P. The HIV-1 Nef protein enhances the affinity of reverse transcriptase for RNA in vitro. Virus Genes. 2002;25:255-69 pubmed
  43. Forshey B, Aiken C. Disassembly of human immunodeficiency virus type 1 cores in vitro reveals association of Nef with the subviral ribonucleoprotein complex. J Virol. 2003;77:4409-14 pubmed
    ..They further suggest that virion-associated Nef may facilitate an early step in HIV-1 infection following dissociation of the viral capsid in the target cell. ..
  44. Greenway A, McPhee D, Allen K, Johnstone R, Holloway G, Mills J, et al. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002;76:2692-702 pubmed
    ..These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis...
  45. Shapira Nahor O, Maayan S, Peden K, Rabinowitz R, Schlesinger M, Alian A, et al. Replication of HIV-1 deleted Nef mutants in chronically immune activated human T cells. Virology. 2002;303:138-45 pubmed
    ..Further activation of these cells by exogenous stimuli enhances replication of the virus. Our results support the notion that Nef enhances the basal level of T cell activation and consequently, viral replication. ..
  46. Fackler O, Alcover A, Schwartz O. Modulation of the immunological synapse: a key to HIV-1 pathogenesis?. Nat Rev Immunol. 2007;7:310-7 pubmed
    ..We propose that modulating lymphocyte signalling, apoptosis and intracellular trafficking ensures efficient spread of the virus in the hostile environment of the immune system. ..
  47. Day J, Munk C, Guatelli J. The membrane-proximal tyrosine-based sorting signal of human immunodeficiency virus type 1 gp41 is required for optimal viral infectivity. J Virol. 2004;78:1069-79 pubmed
  48. Currier J, DeSouza M, Chanbancherd P, Bernstein W, Birx D, Cox J. Comprehensive screening for human immunodeficiency virus type 1 subtype-specific CD8 cytotoxic T lymphocytes and definition of degenerate epitopes restricted by HLA-A0207 and -C(W)0304 alleles. J Virol. 2002;76:4971-86 pubmed
    ..These findings provide biological validation of HLA supertypes in HIV-1 CTL recognition and support earlier studies of cross-subtype CTL responses during HIV-1 infection. ..
  49. Sol Foulon N, Esnault C, Percherancier Y, Porrot F, Metais Cunha P, Bachelerie F, et al. The effects of HIV-1 Nef on CD4 surface expression and viral infectivity in lymphoid cells are independent of rafts. J Biol Chem. 2004;279:31398-408 pubmed
    ..Altogether, these results strongly suggest that rafts are not a key element involved in the effects of Nef on trafficking of cellular proteins and on viral replication. ..
  50. Giese S, Woerz I, Homann S, Tibroni N, Geyer M, Fackler O. Specific and distinct determinants mediate membrane binding and lipid raft incorporation of HIV-1(SF2) Nef. Virology. 2006;355:175-91 pubmed
  51. Addo M, Yu X, Rathod A, Cohen D, Eldridge R, Strick D, et al. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol. 2003;77:2081-92 pubmed
  52. Schiavoni I, Trapp S, Santarcangelo A, Piacentini V, Pugliese K, Baur A, et al. HIV-1 Nef enhances both membrane expression and virion incorporation of Env products. A model for the Nef-dependent increase of HIV-1 infectivity. J Biol Chem. 2004;279:22996-3006 pubmed
    ..In conclusion, we propose that Nef increases the infectivity of HIV-1 at least in part by enhancing the amounts of Env products incorporated into virus particles. ..
  53. Westerhout E, Ooms M, Vink M, Das A, Berkhout B. HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucleic Acids Res. 2005;33:796-804 pubmed
    ..The results highlight the enormous genetic flexibility of HIV-1 and provide detailed molecular insight into the sequence specificity of RNAi and the impact of target RNA secondary structure. ..