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Gene Review

nef  -  nef protein

Simian immunodeficiency virus

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Disease relevance of nef

  • To assess the role of SIV NEF on virus replication and compare its activity with that of its human immunodeficiency virus type 1 counterpart, we examined the activity of an intact nef gene from proviral clone pSIV 102, an isolate from SIV-MAC-251-infected cells [1].
  • We examined the ability of a live, attenuated deletion mutant of simian immunodeficiency virus (SIV), SIVmac239Delta3, which is missing nef and vpr genes, to protect against challenge by heterologous strains SHIV89.6p and SIVsmE660 [2].
  • Similarly, targeting a cytoplasmic protein, HIV-1 nef, to undergo rapid cytoplasmic degradation induced a greatly enhanced de novo nef-specific CD8+ CTL response in vivo after immunization of mice with either recombinant vaccinia vectors or DNA expression plasmids expressing the degradation targeted nef mutant [3].
  • RESULTS: Analysis of multiple viral clones showed nef gene deletions/insertions in 10 out of 15 SP, along with the coexistence of intact and defective nef gene lineages in the same individual over time, whereas these nefgene abnormalities were absent from HIV-1 strains from LTNP [4].
  • DESIGN: Genetic and phylogenetic analyses of the V3 region and the nef gene clones over time from uncultured peripheral blood mononuclear cells (PBMC) of American patients with varying HIV disease progression rates [4].

Psychiatry related information on nef


High impact information on nef


Chemical compound and disease context of nef


Biological context of nef

  • Monkeys were infected experimentally with SIV containing difficult-to-revert mutations in nef that selectively eliminated MHC downregulation but not these other activities [16].
  • Proviral clone pSIV BA was constructed by introducing a premature termination codon at codon 40 of the nef gene without altering the predicted amino acid sequence of the overlapping env gene [1].
  • In addition, it showed that while sequences in the surface portion of the envelope gene determine macrophage tropism, additional sequences derived from the transmembrane portion of envelope and/or nef confer neurovirulence [17].
  • Use of the macaque model of human immunodeficiency virus (HIV) pathogenesis has shown that the accessory genes nef and vpu are important in the pathogenicity of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) [18].
  • In pHP, the long terminal repeats (LTRs), the 5' untranslated leader and portions of the env and nef genes were deleted [19].

Anatomical context of nef


Associations of nef with chemical compounds

  • Viral replication was mapped by in situ hybridization for SIV env, gag, and nef RNA, and catecholaminergic varicosities from the ANS were mapped by sucrose phosphate glyoxylic acid chemofluorescence [23].
  • Sequencing of the env gene of isolates of SHIV-C strains showed conserved amino acid changes in the Env C2 and V3 regions that included changes to negatively charged amino acids, in the cytoplasmic region of gp41 that included a 42 amino acid deletion, and in the Nef protein [24].
  • Serine phosphorylation-independent downregulation of cell-surface CD4 by nef [10].
  • The relation between these two proteins was determined by metabolically labeling transfected COS cells and by deleting the initiator methionine of nef [25].
  • The high affinity of nefGST for glutathione was exploited to develop an assay to identify cellular proteins capable of interacting with nef [26].

Other interactions of nef


Analytical, diagnostic and therapeutic context of nef

  • Sequence analysis revealed a remarkably high level of similarity between their env and nef genes as well as their 3' LTR [28].
  • METHODS: Proviral DNA from longitudinally collected uncultured PBMC were subjected to PCR amplification in the nef gene and env V2 and V3 regions, followed by cloning, sequencing and phylogenetic analysis to establish evolutionary relationships between HIV-1 strains over time [4].
  • In enhancing the HIV-1 cytopathic effect, the deletion of nef might curtail virus production by infected cells, and thus explain in part the reduced viral load observed in vivo in hosts infected with nef-deficient viruses [21].
  • Therefore, during tonsillar SIV Delta nef vaccination, infection is blocked early at the entry portal, which we propose is due in part to innate functions of gamma delta T and dendritic cells [29].
  • Thus, lentivirus-mediated shRNA expression targeting the U3-overlapping region of HIV nef represents a feasible approach to genetic vaccine therapy for HIV-1 [30].


  1. Simian immunodeficiency virus negative factor suppresses the level of viral mRNA in COS cells. Niederman, T.M., Hu, W., Ratner, L. J. Virol. (1991) [Pubmed]
  2. Protection by live, attenuated simian immunodeficiency virus against heterologous challenge. Wyand, M.S., Manson, K., Montefiori, D.C., Lifson, J.D., Johnson, R.P., Desrosiers, R.C. J. Virol. (1999) [Pubmed]
  3. Targeting of HIV-1 antigens for rapid intracellular degradation enhances cytotoxic T lymphocyte (CTL) recognition and the induction of de novo CTL responses in vivo after immunization. Tobery, T.W., Siliciano, R.F. J. Exp. Med. (1997) [Pubmed]
  4. HIV-1 strains from a cohort of American subjects reveal the presence of a V2 region extension unique to slow progressors and non-progressors. Wang, B., Spira, T.J., Owen, S., Lal, R.B., Saksena, N.K. AIDS (2000) [Pubmed]
  5. Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Saito, Y., Sharer, L.R., Epstein, L.G., Michaels, J., Mintz, M., Louder, M., Golding, K., Cvetkovich, T.A., Blumberg, B.M. Neurology (1994) [Pubmed]
  6. HIV pathogenesis: Nef loses control. Foster, J.L., Garcia, J.V. Cell (2006) [Pubmed]
  7. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Kestler, H.W., Ringler, D.J., Mori, K., Panicali, D.L., Sehgal, P.K., Daniel, M.D., Desrosiers, R.C. Cell (1991) [Pubmed]
  8. Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques. Lang, S.M., Iafrate, A.J., Stahl-Hennig, C., Kuhn, E.M., Nisslein, T., Kaup, F.J., Haupt, M., Hunsmann, G., Skowronski, J., Kirchhoff, F. Nat. Med. (1997) [Pubmed]
  9. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Schwartz, O., Maréchal, V., Le Gall, S., Lemonnier, F., Heard, J.M. Nat. Med. (1996) [Pubmed]
  10. Serine phosphorylation-independent downregulation of cell-surface CD4 by nef. Garcia, J.V., Miller, A.D. Nature (1991) [Pubmed]
  11. Simian immunodeficiency virus and human immunodeficiency virus type 1 nef proteins show distinct patterns and mechanisms of Src kinase activation. Greenway, A.L., Dutartre, H., Allen, K., McPhee, D.A., Olive, D., Collette, Y. J. Virol. (1999) [Pubmed]
  12. Chimeric human immunodeficiency virus type 1 virions that contain the simian immunodeficiency virus nef gene are cyclosporin A resistant. Khan, M., Jin, L., Miles, L., Bond, V.C., Powell, M.D. J. Virol. (2005) [Pubmed]
  13. Mechanistic independence of Nef and cyclophilin A enhancement of human immunodeficiency virus type 1 infectivity. Aiken, C. Virology (1998) [Pubmed]
  14. Human immunodeficiency virus type 1 (HIV-1) provirus expression and LTR transcription are repressed in NEF-expressing cell lines. Maitra, R.K., Ahmad, N., Holland, S.M., Venkatesan, S. Virology (1991) [Pubmed]
  15. Genomic Diversity in the Regulatory nef Gene Sequences in Indian Isolates of HIV Type 1: Emergence of a Distinct Subclade and Predicted Implications. Kumar, M., Jain, S.K., Pasha, S.T., Chattopadhaya, D., Lal, S., Rai, A. AIDS Res. Hum. Retroviruses (2006) [Pubmed]
  16. Impact of Nef-mediated downregulation of major histocompatibility complex class I on immune response to simian immunodeficiency virus. Swigut, T., Alexander, L., Morgan, J., Lifson, J., Mansfield, K.G., Lang, S., Johnson, R.P., Skowronski, J., Desrosiers, R. J. Virol. (2004) [Pubmed]
  17. Pathogenesis of simian immunodeficiency virus encephalitis: viral determinants of neurovirulence. Mankowski, J.L., Flaherty, M.T., Spelman, J.P., Hauer, D.A., Didier, P.J., Amedee, A.M., Murphey-Corb, M., Kirstein, L.M., Muñoz, A., Clements, J.E., Zink, M.C. J. Virol. (1997) [Pubmed]
  18. Presence of Intact vpu and nef genes in nonpathogenic SHIV is essential for acquisition of pathogenicity of this virus by serial passage in macaques. Mackay, G.A., Niu, Y., Liu, Z.Q., Mukherjee, S., Li, Z., Adany, I., Buch, S., Zhuge, W., McClure, H.M., Narayan, O., Smith, M.S. Virology (2002) [Pubmed]
  19. Efficacy and safety analyses of a recombinant human immunodeficiency virus type 1 derived vector system. Chang, L.J., Urlacher, V., Iwakuma, T., Cui, Y., Zucali, J. Gene Ther. (1999) [Pubmed]
  20. CD4-independent entry and replication of simian immunodeficiency virus in primary rhesus macaque astrocytes are regulated by the transmembrane protein. Overholser, E.D., Babas, T., Zink, M.C., Barber, S.A., Clements, J.E. J. Virol. (2005) [Pubmed]
  21. The nef gene controls syncytium formation in primary human lymphocytes and macrophages infected by HIV type 1. Meylan, P.R., Baumgartner, M., Ciuffi, A., Munoz, M., Sahli, R. AIDS Res. Hum. Retroviruses (1998) [Pubmed]
  22. Production of a non-functional nef protein in human immunodeficiency virus type 1-infected CEM cells. Laurent, A.G., Hovanessian, A.G., Rivière, Y., Krust, B., Regnault, A., Montagnier, L., Findeli, A., Kieny, M.P., Guy, B. J. Gen. Virol. (1990) [Pubmed]
  23. Enhanced replication of simian immunodeficiency virus adjacent to catecholaminergic varicosities in primate lymph nodes. Sloan, E.K., Tarara, R.P., Capitanio, J.P., Cole, S.W. J. Virol. (2006) [Pubmed]
  24. A highly pathogenic simian/human immunodeficiency virus with genetic changes in cynomolgus monkey. Shinohara, K., Sakai, K., Ando, S., Ami, Y., Yoshino, N., Takahashi, E., Someya, K., Suzaki, Y., Nakasone, T., Sasaki, Y., Kaizu, M., Lu, Y., Honda, M. J. Gen. Virol. (1999) [Pubmed]
  25. Genetic characterization of human immunodeficiency virus type 1 nef gene products translated in vitro and expressed in mammalian cells. Kaminchik, J., Bashan, N., Itach, A., Sarver, N., Gorecki, M., Panet, A. J. Virol. (1991) [Pubmed]
  26. Identification of cellular proteins that bind to the human immunodeficiency virus type 1 nef gene product in vitro: a role for myristylation. Harris, M., Coates, K. J. Gen. Virol. (1993) [Pubmed]
  27. Functional association between the nef gene product and gag-pol region of HIV-1. Ono, T., Iwatani, Y., Nishimura, A., Ishimoto, A., Sakai, H. FEBS Lett. (2000) [Pubmed]
  28. Development and characterization of positively selected brain-adapted SIV. Gaskill, P.J., Watry, D.D., Burdo, T.H., Fox, H.S. Virol. J. (2005) [Pubmed]
  29. Early protection against pathogenic virus infection at a mucosal challenge site after vaccination with attenuated simian immunodeficiency virus. Tenner-Racz, K., Stahl Hennig, C., Uberla, K., Stoiber, H., Ignatius, R., Heeney, J., Steinman, R.M., Racz, P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  30. Lentivirus vectors expressing short hairpin RNAs against the U3-overlapping region of HIV nef inhibit HIV replication and infectivity in primary macrophages. Yamamoto, T., Miyoshi, H., Yamamoto, N., Yamamoto, N., Inoue, J., Tsunetsugu-Yokota, Y. Blood (2006) [Pubmed]
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