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Gene Review

nef  -  p27

Human immunodeficiency virus 1

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Disease relevance of nef

  • Depending on the genes studied, phylogenetic analysis showed that YBF30 branched either with SIVcpz-gab or between SIVcpz-gab and HIV-1 group M. The structural genes and tat, vpr, and nef of YBF30 are approximately equidistant from those of HIV-1 group M and SIVcpz-gab [1].
  • Here, we report that HIV infection leads to selective transcription of the nef and tat genes before integration [2].
  • We report the complete sequence analysis of the provirus harbored in a long-term nonprogressor (patient SG1) 20 years after the first infection with a human immunodeficiency virus type 1 strain lacking nef [3].
  • Notably, nef alleles from AIDS patients were more effective in preventing superinfection than those derived from a nonprogressor of HIV-1 infection [4].
  • To circumvent these issues, a novel chimeric polyprotein vaccine candidate (Retanef), comprising genetically modified and re-assorted rev, tat, and nef open reading frames of simian immunodeficiency virus (SIV), was constructed and optimized for its expression in mammalian cells [5].

Psychiatry related information on nef

  • We have cloned 97 nef genes and characterized 10 Nef proteins from autopsy brain and lymphoid tissues from 2 patients with AIDS and HIV-1-associated dementia [6].
  • The results suggest that although the evolution of other loci is inversely correlated to the onset and rate of clinical disease, differential evolution of nef is related neither to drug abuse nor to rapid progression within the first 20 weeks of infection [7].
  • Unlike our earlier studies of tat and env, nef evolution was not affected by morphine abuse or by rapid disease progression [7].
  • We report here that the addition of MG132 or lactacystin, each a specific inhibitor of cellular proteasome activity, preferentially enhances cellular permissiveness to infection by Nef-defective versus wild-type HIV-1 [8].
  • Anomalies in Nef expression within the central nervous system of HIV-1 positive individuals/AIDS patients with or without AIDS dementia complex [9].

High impact information on nef


Chemical compound and disease context of nef


Biological context of nef


Anatomical context of nef

  • Here, we performed a structure-function analysis of the Nef protein by comparing the effect on T-cell development of different nef alleles, either wild type or defective for selected functions, expressed by human thymocytes [21].
  • We have previously shown that an env and nef deleted HIV-1 vector (HIV-1 delta EN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34(+) precursors of DCs [22].
  • The HIV-1 gene nef is important for progression toward AIDS and cellular depletion of the infected thymus [21].
  • These findings indicate that vpr and nef each can induce podocyte injury with a prominent synergistic interaction [17].
  • The relevance of the accessory vpr, vpu, and nef genes for human immunodeficiency virus type 1 (HIV-1) replication in human lymphoid tissue (HLT), the major site of viral replication in vivo, is largely unknown [23].

Associations of nef with chemical compounds


Physical interactions of nef


Regulatory relationships of nef

  • The Nef-induced translocation of Eed led to a potent stimulation of Tat-dependent HIV transcription, implying that Eed removal from the nucleus is required for optimal Tat function [12].
  • Consistent with these quantitative differences, Nef inhibited superinfection more efficiently than Vpu and Env [4].
  • Similarly, cells transduced with LrevSN were able to rescue a rev- HIV-1 provirus, indicating the presence of a functional Rev. We also used LnefSN to obtain clones of cells expressing Nef [29].
  • ENF resistance mutations, selected in vitro or in vivo, were introduced into the env gene of HIV-1(NL4-3) by site-directed mutagenesis and expressed in HIV-1 recombinants carrying sequence tags in nef [30].

Other interactions of nef

  • In support of this possibility, mutations at rev 3' splice site A4b AG dinucleotide dramatically increased splicing of the env/nef 3' splice site A5 [31].
  • For testing effects of simultaneous expression of vpr and nef, these two lines were mated [17].
  • Vif, Vpu and Nef as a fusion protein with proteolytic cleavage sites (VVN-P) is able to induce a significant level of cellular immune responses [32].
  • RESULTS: DNA vaccine construct (pVVN-P) expressing Vif, Vpu and Nef was processed and the fusion protein was cleaved appropriately [32].
  • VRC-HIVDNA009-00-VP is a 4-plasmid mixture encoding subtype B Gag-Pol-Nef fusion protein and modified envelope (Env) constructs from subtypes A, B, and C. Fifty healthy, uninfected adults were randomized to receive either placebo (n=10) or study vaccine at 2 mg (n=5), 4 mg (n=20), or 8 mg (n=15) by needle-free intramuscular injection [33].

Analytical, diagnostic and therapeutic context of nef


  1. Identification of a new human immunodeficiency virus type 1 distinct from group M and group O. Simon, F., Mauclère, P., Roques, P., Loussert-Ajaka, I., Müller-Trutwin, M.C., Saragosti, S., Georges-Courbot, M.C., Barré-Sinoussi, F., Brun-Vézinet, F. Nat. Med. (1998) [Pubmed]
  2. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Wu, Y., Marsh, J.W. Science (2001) [Pubmed]
  3. Entire Genome of a Strain of Human Immunodeficiency Virus Type 1 with a Deletion of nef That Was Recovered 20 Years after Primary Infection: Large Pool of Proviruses with Deletions of env. Calugi, G., Montella, F., Favalli, C., Benedetto, A. J. Virol. (2006) [Pubmed]
  4. Contribution of Vpu, Env, and Nef to CD4 down-modulation and resistance of human immunodeficiency virus type 1-infected T cells to superinfection. Wildum, S., Schindler, M., Münch, J., Kirchhoff, F. J. Virol. (2006) [Pubmed]
  5. A novel chimeric Rev, Tat, and Nef (Retanef) antigen as a component of an SIV/HIV vaccine. Hel, Z., Johnson, J.M., Tryniszewska, E., Tsai, W.P., Harrod, R., Fullen, J., Tartaglia, J., Franchini, G. Vaccine (2002) [Pubmed]
  6. CD4 and MHC-I downregulation are conserved in primary HIV-1 Nef alleles from brain and lymphoid tissues, but Pak2 activation is highly variable. Agopian, K., Wei, B.L., Garcia, J.V., Gabuzda, D. Virology (2007) [Pubmed]
  7. Lack of correlation between SIV-Nef evolution and rapid disease progression in morphine-dependent nonhuman primate model of AIDS. Noel, R.J., Toro-Bahamonde, A., Marrero-Otero, Z., Orsini, S., Verma, A.S., Kumar, R., Kumar, A. AIDS Res. Hum. Retroviruses (2006) [Pubmed]
  8. Selective restriction of Nef-defective human immunodeficiency virus type 1 by a proteasome-dependent mechanism. Qi, M., Aiken, C. J. Virol. (2007) [Pubmed]
  9. Anomalies in Nef expression within the central nervous system of HIV-1 positive individuals/AIDS patients with or without AIDS dementia complex. McPhee, D.A., Greenway, A.L., Holloway, G., Smith, K., Deacon, N., Pemberton, L., Brew, B.J. J. Neurovirol. (1998) [Pubmed]
  10. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Schindler, M., Münch, J., Kutsch, O., Li, H., Santiago, M.L., Bibollet-Ruche, F., Müller-Trutwin, M.C., Novembre, F.J., Peeters, M., Courgnaud, V., Bailes, E., Roques, P., Sodora, D.L., Silvestri, G., Sharp, P.M., Hahn, B.H., Kirchhoff, F. Cell (2006) [Pubmed]
  11. HIV pathogenesis: Nef loses control. Foster, J.L., Garcia, J.V. Cell (2006) [Pubmed]
  12. HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane. Witte, V., Laffert, B., Rosorius, O., Lischka, P., Blume, K., Galler, G., Stilper, A., Willbold, D., D'Aloja, P., Sixt, M., Kolanus, J., Ott, M., Kolanus, W., Schuler, G., Baur, A.S. Mol. Cell (2004) [Pubmed]
  13. Modulation of cellular protein trafficking by human immunodeficiency virus type 1 Nef: role of the acidic residue in the ExxxLL motif. Coleman, S.H., Madrid, R., Van Damme, N., Mitchell, R.S., Bouchet, J., Servant, C., Pillai, S., Benichou, S., Guatelli, J.C. J. Virol. (2006) [Pubmed]
  14. HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor. Vigerust, D.J., Egan, B.S., Shepherd, V.L. J. Leukoc. Biol. (2005) [Pubmed]
  15. Constitutive expression of human immunodeficiency virus (HIV) nef protein in human astrocytes does not influence basal or induced HIV long terminal repeat activity. Bachelerie, F., Alcami, J., Hazan, U., Israël, N., Goud, B., Arenzana-Seisdedos, F., Virelizier, J.L. J. Virol. (1990) [Pubmed]
  16. Epitopes of human immunodeficiency virus regulatory proteins tat, nef and rev are expressed in skin in atopic dermatitis. Schuurman, H.J., Joling, P., van Wichen, D.F., Tobin, D., van der Putte, S.C. Int. Arch. Allergy Immunol. (1993) [Pubmed]
  17. HIV-1 Genes vpr and nef Synergistically Damage Podocytes, Leading to Glomerulosclerosis. Zuo, Y., Matsusaka, T., Zhong, J., Ma, J., Ma, L.J., Hanna, Z., Jolicoeur, P., Fogo, A.B., Ichikawa, I. J. Am. Soc. Nephrol. (2006) [Pubmed]
  18. HIV-1 Nef induces proliferation and anchorage-independent growth in podocytes. Husain, M., Gusella, G.L., Klotman, M.E., Gelman, I.H., Ross, M.D., Schwartz, E.J., Cara, A., Klotman, P.E. J. Am. Soc. Nephrol. (2002) [Pubmed]
  19. Defective accessory genes in a human immunodeficiency virus type 1-infected long-term survivor lacking recoverable virus. Michael, N.L., Chang, G., d'Arcy, L.A., Ehrenberg, P.K., Mariani, R., Busch, M.P., Birx, D.L., Schwartz, D.H. J. Virol. (1995) [Pubmed]
  20. Genetic instability of live, attenuated human immunodeficiency virus type 1 vaccine strains. Berkhout, B., Verhoef, K., van Wamel, J.L., Back, N.K. J. Virol. (1999) [Pubmed]
  21. Signaling but not trafficking function of HIV-1 protein Nef is essential for Nef-induced defects in human intrathymic T-cell development. Stove, V., Naessens, E., Stove, C., Swigut, T., Plum, J., Verhasselt, B. Blood (2003) [Pubmed]
  22. Dendritic cells transduced by multiply deleted HIV-1 vectors exhibit normal phenotypes and functions and elicit an HIV-specific cytotoxic T-lymphocyte response in vitro. Gruber, A., Kan-Mitchell, J., Kuhen, K.L., Mukai, T., Wong-Staal, F. Blood (2000) [Pubmed]
  23. Vpr and Vpu are important for efficient human immunodeficiency virus type 1 replication and CD4+ T-cell depletion in human lymphoid tissue ex vivo. Rücker, E., Grivel, J.C., Münch, J., Kirchhoff, F., Margolis, L. J. Virol. (2004) [Pubmed]
  24. HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Drakesmith, H., Chen, N., Ledermann, H., Screaton, G., Townsend, A., Xu, X.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Nef-induced alteration of the early/recycling endosomal compartment correlates with enhancement of HIV-1 infectivity. Madrid, R., Janvier, K., Hitchin, D., Day, J., Coleman, S., Noviello, C., Bouchet, J., Benmerah, A., Guatelli, J., Benichou, S. J. Biol. Chem. (2005) [Pubmed]
  26. HIV-1 Nef stabilizes the association of adaptor protein complexes with membranes. Janvier, K., Craig, H., Hitchin, D., Madrid, R., Sol-Foulon, N., Renault, L., Cherfils, J., Cassel, D., Benichou, S., Guatelli, J. J. Biol. Chem. (2003) [Pubmed]
  27. Human immunodeficiency virus type 1 Nef domains required for disruption of major histocompatibility complex class I trafficking are also necessary for coprecipitation of Nef with HLA-A2. Williams, M., Roeth, J.F., Kasper, M.R., Filzen, T.M., Collins, K.L. J. Virol. (2005) [Pubmed]
  28. Human immunodeficiency virus-1 Nef protein interacts with Tat and enhances HIV-1 gene expression. Joseph, A.M., Ladha, J.S., Mojamdar, M., Mitra, D. FEBS Lett. (2003) [Pubmed]
  29. Retrovirus vector-mediated transfer of functional HIV-1 regulatory genes. Garcia, J.V., Miller, A.D. AIDS Res. Hum. Retroviruses (1994) [Pubmed]
  30. Relative replicative fitness of human immunodeficiency virus type 1 mutants resistant to enfuvirtide (T-20). Lu, J., Sista, P., Giguel, F., Greenberg, M., Kuritzkes, D.R. J. Virol. (2004) [Pubmed]
  31. Overlapping cis sites used for splicing of HIV-1 env/nef and rev mRNAs. Swanson, A.K., Stoltzfus, C.M. J. Biol. Chem. (1998) [Pubmed]
  32. Immunogenicity of a novel DNA vaccine cassette expressing multiple human immunodeficiency virus (HIV-1) accessory genes. Ayyavoo, V., Kudchodkar, S., Ramanathan, M.P., Le, P., Muthumani, K., Megalai, N.M., Dentchev, T., Santiago-Barrios, L., Mrinalini, C., Weiner, D.B. AIDS (2000) [Pubmed]
  33. Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV-1 DNA Candidate Vaccine. Graham, B.S., Koup, R.A., Roederer, M., Bailer, R.T., Enama, M.E., Moodie, Z., Martin, J.E., McCluskey, M.M., Chakrabarti, B.K., Lamoreaux, L., Andrews, C.A., Gomez, P.L., Mascola, J.R., Nabel, G.J. J. Infect. Dis. (2006) [Pubmed]
  34. Nef-mediated resistance of human immunodeficiency virus type 1 to antiviral cytotoxic T lymphocytes. Yang, O.O., Nguyen, P.T., Kalams, S.A., Dorfman, T., Göttlinger, H.G., Stewart, S., Chen, I.S., Threlkeld, S., Walker, B.D. J. Virol. (2002) [Pubmed]
  35. DNA vaccination in mice using HIV-1 nef, rev and tat genes in self-replicating pBN-vector. Tähtinen, M., Strengell, M., Collings, A., Pitkänen, J., Kjerrström, A., Hakkarainen, K., Peterson, P., Kohleisen, B., Wahren, B., Ranki, A., Ustav, M., Krohn, K. Vaccine (2001) [Pubmed]
  36. HIV-1 Nef promotes survival of TF-1 macrophages by inducing Bcl-XL expression in an extracellular signal-regulated kinase-dependent manner. Choi, H.J., Smithgall, T.E. J. Biol. Chem. (2004) [Pubmed]
  37. Expression kinetics and subcellular localization of HIV-1 regulatory proteins Nef, Tat and Rev in acutely and chronically infected lymphoid cell lines. Ranki, A., Lagerstedt, A., Ovod, V., Aavik, E., Krohn, K.J. Arch. Virol. (1994) [Pubmed]
  38. Persistent infection of MT-4 cells by human immunodeficiency virus type 1 becomes increasingly likely with in vitro serial passage of wild-type but not nef mutant virus. Nishino, Y., Nakaya, T., Fujinaga, K., Kishi, M., Azuma, I., Ikuta, K. J. Gen. Virol. (1994) [Pubmed]
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