nef genes


Summary: DNA sequences that form the coding region for a protein that down-regulates the expression of human immunodeficiency virus (HIV). nef is short for negative factor.

Top Publications

  1. Gao F, Li Y, Decker J, Peyerl F, Bibollet Ruche F, Rodenburg C, et al. Codon usage optimization of HIV type 1 subtype C gag, pol, env, and nef genes: in vitro expression and immune responses in DNA-vaccinated mice. AIDS Res Hum Retroviruses. 2003;19:817-23 pubmed
    ..the generation and biological characterization of codon usage-optimized gag, pol, env (gp160, gp140, gp120), and nef genes from a primary (nonrecombinant) HIV-1 subtype C isolate...
  2. Chassin D, Andrieu M, Cohen W, Culmann Penciolelli B, Ostankovitch M, Hanau D, et al. Dendritic cells transfected with the nef genes of HIV-1 primary isolates specifically activate cytotoxic T lymphocytes from seropositive subjects. Eur J Immunol. 1999;29:196-202 pubmed
    ..To evaluate the presentation of peptides derived from viral antigen to CTL, we transfected nef genes obtained from peripheral blood mononuclear cells of HIV-1-seropositive subjects into dendritic cells isolated ..
  3. Westerhout E, Vink M, Haasnoot P, Das A, Berkhout B. A conditionally replicating HIV-based vector that stably expresses an antiviral shRNA against HIV-1 replication. Mol Ther. 2006;14:268-75 pubmed
    ..Because the shRNA targets viral sequences that are removed from the vector construct, there is no self-targeting, yet there is specific shutdown of HIV-1 replication. ..
  4. Ter Brake O, Konstantinova P, Ceylan M, Berkhout B. Silencing of HIV-1 with RNA interference: a multiple shRNA approach. Mol Ther. 2006;14:883-92 pubmed
    ..These results confirm that RNAi has great potential as an antiviral gene therapy approach and support our efforts to develop this strategy for treatment of HIV-1-infected individuals. ..
  5. Cho Y, Lim J, Jung Y, Oh S, Lee H, Sung H. High frequency of grossly deleted nef genes in HIV-1 infected long-term slow progressors treated with Korean red ginseng. Curr HIV Res. 2006;4:447-57 pubmed
    ..between Korean red ginseng (KRG) intake in HIV-1 infected patients and the occurrence of grossly deleted nef genes (gDeltanef), we characterized nef genes in 10 long-term slow progressors (LTSP) infected with HIV-1 subtype B ..
  6. Rhodes D, Ashton L, Solomon A, Carr A, Cooper D, Kaldor J, et al. Characterization of three nef-defective human immunodeficiency virus type 1 strains associated with long-term nonprogression. Australian Long-Term Nonprogressor Study Group. J Virol. 2000;74:10581-8 pubmed
    ..All three strains of virus had envelope sequences characteristic of macrophagetropic viruses. These findings further indicate the reduced pathogenic potential of nef-defective viruses. ..
  7. Hel Z, Tryniszewska E, Tsai W, Johnson J, Harrod R, Fullen J, et al. Design and in vivo immunogenicity of a polyvalent vaccine based on SIVmac regulatory genes. DNA Cell Biol. 2002;21:619-26 pubmed
    ..An equivalent strategy may be used for the generation of polyvalent antigens encoding the regulatory proteins in a HIV-1 vaccine candidate. ..
  8. Haas G, Plikat U, Debre P, Lucchiari M, Katlama C, Dudoit Y, et al. Dynamics of viral variants in HIV-1 Nef and specific cytotoxic T lymphocytes in vivo. J Immunol. 1996;157:4212-21 pubmed
    ..Therefore, a remarkable flexibility of the immune system allows constant adaptation of CTL to multiple HIV variants and thus elimination of HIV variant-producing cells in slow progressors. ..
  9. Brumme Z, Brumme C, Carlson J, Streeck H, John M, Eichbaum Q, et al. Marked epitope- and allele-specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection. J Virol. 2008;82:9216-27 pubmed publisher
    ..Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response. ..

More Information


  1. Wyatt C, Rosenstiel P, Klotman P. HIV-associated nephropathy. Contrib Nephrol. 2008;159:151-61 pubmed publisher
    ..Future therapies could also target different steps in the pathogenesis of HIVAN, including viral replication, epithelial cell entry and viral gene expression, and downstream cellular pathways. ..
  2. Alexander L, Illyinskii P, Lang S, Means R, Lifson J, Mansfield K, et al. Determinants of increased replicative capacity of serially passaged simian immunodeficiency virus with nef deleted in rhesus monkeys. J Virol. 2003;77:6823-35 pubmed
    ..These results delineate sequence changes in SIV that can compensate for the loss of the nef gene to partially restore replicative and pathogenic potential in rhesus monkeys. ..
  3. Binninger Schinzel D, Norley S, Adler H, Oberg H, Kurth R. Simian immunodeficiency viruses with defective nef genes show increased susceptibility to the noncytotoxic antiviral activity of CD8+ lymphocytes. Virology. 2002;294:209-21 pubmed
  4. Das A, Verhoef K, Berkhout B. A conditionally replicating virus as a novel approach toward an HIV vaccine. Methods Enzymol. 2004;388:359-79 pubmed
  5. Chakraborty R, Morel A, Sutton J, Appay V, Ripley R, Dong T, et al. Correlates of delayed disease progression in HIV-1-infected Kenyan children. J Immunol. 2005;174:8191-9 pubmed
    ..As HIV-1-specific helper cells support anti-HIV-1 effector responses in active disease, their presence may be important in delaying disease progression. ..
  6. Yamamoto T, Isogai M, Otake K, Tsunetsugu Yokota Y. High and inducible expression of human immunodeficiency virus type 1 (HIV-1) Nef by adenovirus vector does not disturb potent antigen presentation by monocyte-derived dendritic cells. Microbes Infect. 2006;8:2522-30 pubmed
    ..Therefore, although adenovirus vector may modulate some aspects of MDDC function, Nef-expressing adenovirus would be served as one of HIV vaccine candidates. ..
  7. Calugi G, Montella F, Favalli C, Benedetto A. 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. J Virol. 2006;80:11892-6 pubmed
  8. Dickie P. Nef modulation of HIV type 1 gene expression and cytopathicity in tissues of HIV transgenic mice. AIDS Res Hum Retroviruses. 2000;16:777-90 pubmed
    ..This HIV proviral transgenic model has demonstrated the capacity of HIV-1 Nef to contribute to HIV cytopathicity by altering cellular maturation and viral gene expression in vivo. ..
  9. Cho Y, Jung Y, Sung H. Frequent gross deletion in the HIV type 1 nef gene in hemophiliacs treated with Korean Red Ginseng: inhibition of detection by highly active antiretroviral therapy. AIDS Res Hum Retroviruses. 2009;25:419-24 pubmed publisher
    ..5%) (p < 0.05). These finding suggest that the frequency of gDeltanef is dependent on the amount of KRG intake, although further study is needed. These data might provide a new perspective on the pathogenesis of HIV-1. ..
  10. Mustafa F, Robinson H. Context-dependent role of human immunodeficiency virus type 1 auxiliary genes in the establishment of chronic virus producers. J Virol. 1993;67:6909-15 pubmed
    ..These results suggest that complex interactions of viral auxiliary and nonauxiliary gene functions with the host cell determine the ability to establish chronic virus producers. ..
  11. Azad A. Could Nef and Vpr proteins contribute to disease progression by promoting depletion of bystander cells and prolonged survival of HIV-infected cells?. Biochem Biophys Res Commun. 2000;267:677-85 pubmed
  12. Zanotto P, Kallas E, de Souza R, Holmes E. Genealogical evidence for positive selection in the nef gene of HIV-1. Genetics. 1999;153:1077-89 pubmed
    ..Mapping the locations of positively selected sites may also be of use in identifying targets of the immune response and hence aid vaccine design. ..
  13. Tobiume M, Tokunaga K, Kiyokawa E, Takahoko M, Mochizuki N, Tatsumi M, et al. Requirement of nef for HIV-1 infectivity is biased by the expression levels of Env in the virus-producing cells and CD4 in the target cells. Arch Virol. 2001;146:1739-51 pubmed
    ..Thus, we propose that Env on the virion and CD4 on the target cells have inhibitory effects on the post-entry step of the HIV-1 replication cycle, and that Nef functions to counteract this negative effect. ..
  14. Collette Y, Mawas C, Olive D. Evidence for intact CD28 signaling in T cell hyporesponsiveness induced by the HIV-1 nef gene. Eur J Immunol. 1996;26:1788-93 pubmed
    ..These data agree with the T cell defects observed in PBMC isolated from HIV-infected individuals. ..
  15. Lichterfeld M, Yu X, Cohen D, Addo M, Malenfant J, Perkins B, et al. HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity. AIDS. 2004;18:1383-92 pubmed
    ..Later diversification of responses to other proteins during prolonged antigen exposure provides evidence of the initial preferential immunogenicity of Nef epitopes compared to similarly conserved regions within other viral proteins. ..
  16. Cazeaux N, Bennasser Y, Vidal P, Li Z, Paulin D, Bahraoui E. Comparative study of immune responses induced after immunization with plasmids encoding the HIV-1 Nef protein under the control of the CMV-IE or the muscle-specific desmin promoter. Vaccine. 2002;20:3322-31 pubmed
    ..In conclusion, these data indicate that antigen expression by muscle cells is sufficient to stimulate a Th1 immune response. ..
  17. Orita S, Sato S, Aono Y, Minoura N, Yamashita T, Hinuma Y, et al. Identification of novel singly spliced pX mRNA transcripts common to all human T-cell leukemia virus type 1-related retroviruses. Virus Genes. 1993;7:197-204 pubmed
    ..This novel mRNA in the HTLV-1-related virus group may be analogous to the two-exon nef specific mRNA in human immunodeficiency virus type 1...
  18. Benichou S, Benmerah A. [The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]. Med Sci (Paris). 2003;19:100-6 pubmed
    ..In addition, these viral factors represent valuable tools to study the pathway they are perturbing. ..
  19. Bertsch C, Cluet D, Beyer C, Gloeckler L, Cecile A, Gut J, et al. Properties of a chimeric simian-human immunodeficiency virus expressing an hybrid HIV-1 Nef/SIVmac Nef protein. Arch Virol. 2002;147:1963-75 pubmed
    The nef genes of human and simian immunodeficiency viruses code for a membrane associated protein critical for AIDS development. SIVmac Nef presents C-terminal a 27 amino acid extension absent of HIV-1 Nef...
  20. Mazzolini J, Herit F, Bouchet J, Benmerah A, Benichou S, Niedergang F. Inhibition of phagocytosis in HIV-1-infected macrophages relies on Nef-dependent alteration of focal delivery of recycling compartments. Blood. 2010;115:4226-36 pubmed publisher
    ..We conclude that HIV-1 impairs optimal phagosome formation through Nef-dependent perturbation of the endosomal remodeling relying on AP1. We therefore identified a mechanism of macrophage function down-regulation in infected cells. ..
  21. Cho Y, Foley B, Sung H, Kim Y, Kim J. Molecular epidemiologic study of a human immunodeficiency virus 1 outbreak in haemophiliacs B infected through clotting factor 9 after 1990. Vox Sang. 2007;92:113-20 pubmed
    ..A clotting factor made in Korea from blood from cash-paid donors infected at least 20 haemophiliacs with HIV-1 subtype B. ..
  22. Schindler M, Wildum S, Casartelli N, Doria M, Kirchhoff F. Nef alleles from children with non-progressive HIV-1 infection modulate MHC-II expression more efficiently than those from rapid progressors. AIDS. 2007;21:1103-7 pubmed
    It has been established that defective nef genes and differences in the Nef-mediated downmodulation of CD4 and MHC-I cell surface expression can be associated with different rates of HIV-1 disease progression...
  23. Munch J, Janardhan A, Stolte N, Stahl Hennig C, ten Haaft P, Heeney J, et al. T-cell receptor:CD3 down-regulation is a selected in vivo function of simian immunodeficiency virus Nef but is not sufficient for effective viral replication in rhesus macaques. J Virol. 2002;76:12360-4 pubmed
    ..Additional mutations elsewhere in SIVmac239 tnef genomes are required for a virulent phenotype. ..
  24. Nishino Y, Nakaya T, Fujinaga K, Kishi M, Azuma I, Ikuta K. 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. J Gen Virol. 1994;75 ( Pt 9):2241-51 pubmed
    ..Our results also suggest an important role for the nef gene product in the generation of HIV-1 strains that are less cytopathogenic. ..
  25. Rousseau C, Abrams E, Lee M, Urbano R, King M. Long terminal repeat and nef gene variants of human immunodeficiency virus type 1 in perinatally infected long-term survivors and rapid progressors. AIDS Res Hum Retroviruses. 1997;13:1611-23 pubmed
    ..Mutations of the SP1-III site in a rapid progressor (RP056) indicate that this site is not necessary for rapid disease progression. ..
  26. Simard M, Chrobak P, Kay D, Hanna Z, Jothy S, Jolicoeur P. Expression of simian immunodeficiency virus nef in immune cells of transgenic mice leads to a severe AIDS-like disease. J Virol. 2002;76:3981-95 pubmed
    ..These Tg mice should be instrumental in studying the pathogenesis of SIV Nef-induced phenotypes. ..
  27. 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. ..
  28. Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, et al. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001;7:1217-24 pubmed
    ..Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis. ..
  29. Lu J, Kuritzkes D. A novel recombinant marker virus assay for comparing the relative fitness of hiv-1 reverse transcriptase variants. J Acquir Immune Defic Syndr. 2001;27:7-13 pubmed
    ..With appropriate modification of the recombination vectors, the RMVA should be useful for analyzing the fitness of viruses resistant to protease, integrase, or fusion inhibitors and should be applicable in clinical research. ..
  30. Kozyrev I, Miura T, Haga T, Kuwata T, Hayami M. Construction of SIV/HIV-1 chimeric viruses having the IL-5 gene and determination of their ability to replicate and produce IL-5. Arch Virol. 2001;146:1051-62 pubmed
    ..These results show that co-expression of IL-5 stimulates SHIV replication in vitro. Thus, it is expected that expression of IL-5 will also have an effect on viral replication and pathogenicity in vivo. ..
  31. Stahl Hennig C, Steinman R, ten Haaft P, Uberla K, Stolte N, Saeland S, et al. The simian immunodeficiency virus deltaNef vaccine, after application to the tonsils of Rhesus macaques, replicates primarily within CD4(+) T cells and elicits a local perforin-positive CD8(+) T-cell response. J Virol. 2002;76:688-96 pubmed
    ..In fact, this immunodeficiency virus can replicate actively in CD4(+) T cells prior to being contained by the host, at least in part by a strong killer cell response that is generated acutely in the infected lymph nodes. ..
  32. Anastassopoulou C, Kostrikis L. Viral correlates of HIV-1 disease. Curr HIV Res. 2005;3:113-32 pubmed
    ..Unraveling these roles is expected to aid the continued quest for truly effective antiretroviral drug regimens and preventive vaccines. ..
  33. Fang Z, Limbach K, Tartaglia J, Hammonds J, Chen X, Spearman P. Expression of vaccinia E3L and K3L genes by a novel recombinant canarypox HIV vaccine vector enhances HIV-1 pseudovirion production and inhibits apoptosis in human cells. Virology. 2001;291:272-84 pubmed
    ..The addition of immunomodulatory genes to attenuated poxviruses represents a novel strategy for enhancing antigen production by live vector HIV vaccine candidates...
  34. Jere A, Tripathy S, Agnihotri K, Jadhav S, Paranjape R. Genetic analysis of Indian HIV-1 nef: subtyping, variability and implications. Microbes Infect. 2004;6:279-89 pubmed
    ..Hence these data would be useful in designing Nef epitopes to be included in multi-epitope HIV-1 vaccine for the Indian population and would also be of immense help in HIV-1 evolutionary studies. ..
  35. Jeeninga R, Jan B, van der Linden B, van den Berg H, Berkhout B. Construction of a minimal HIV-1 variant that selectively replicates in leukemic derived T-cell lines: towards a new virotherapy approach. Cancer Res. 2005;65:3347-55 pubmed
    ..The mini-HIV variant that uses CD4 and CXCR4 for cell entry could potentially be used against CXCR4-expressing malignancies such as T-lymphoblastic leukemia/lymphoma, natural killer leukemia, and some myeloid leukemias. ..
  36. Priceputu E, Rodrigue I, Chrobak P, Poudrier J, Mak T, Hanna Z, et al. The Nef-mediated AIDS-like disease of CD4C/human immunodeficiency virus transgenic mice is associated with increased Fas/FasL expression on T cells and T-cell death but is not prevented in Fas-, FasL-, tumor necrosis factor receptor 1-, or interleuki. J Virol. 2005;79:6377-91 pubmed
    ..In view of the high resemblance between numerous phenotypes observed in the CD4C/HIV Tg mice and in human AIDS, our findings are likely to be relevant for the human disease. ..
  37. Trono D, Wang J. Nef and PAK: virulence factor and cellular accomplice. Chem Biol. 1997;4:13-5 pubmed
    ..The Nef protein is important in HIV replication and in AIDS pathogenesis. The finding that Nef activates a member of the PAK family of protein kinases provides new insights into the mechanisms of action of this critical virulence factor. ..
  38. Saurya S, Lichtenstein Z, Karpas A. Characterization of nef gene of HIV type 1 in highly active antiretroviral therapy treated AIDS patients with discordance between viral load and CD4+ T cell counts. AIDS Res Hum Retroviruses. 2002;18:983-7 pubmed
    ..The sequences were aligned and compared with other strains of HIV-1. Various substitutions were seen in most patients; however, two patients showed unique insertions of different sizes that are probably due to HAART. ..
  39. Novembre F, de Rosayro J, O Neil S, Anderson D, Klumpp S, McClure H. Isolation and characterization of a neuropathogenic simian immunodeficiency virus derived from a sooty mangabey. J Virol. 1998;72:8841-51 pubmed
    ..This virus should provide an excellent system for investigating the mechanism of lentivirus-induced neurologic disease...
  40. Ellenberger D, Sullivan P, Dorn J, Schable C, Spira T, Folks T, et al. Viral and immunologic examination of human immunodeficiency virus type 1-infected, persistently seronegative persons. J Infect Dis. 1999;180:1033-42 pubmed
    ..These data suggest that the lack of a detectable antibody response in these patients may be the result of immune dysfunction. ..
  41. Overholser E, Babas T, Zink M, Barber S, Clements J. CD4-independent entry and replication of simian immunodeficiency virus in primary rhesus macaque astrocytes are regulated by the transmembrane protein. J Virol. 2005;79:4944-51 pubmed
    ..that the genetic determinants of simian immunodeficiency virus (SIV) neurovirulence map to the env and nef genes. Recent studies from our laboratory demonstrated that SIV replication in primary rhesus macaque astrocyte ..
  42. Emori Y, Ikeda T, Ohashi T, Masuda T, Kurimoto T, Takei M, et al. Inhibition of human immunodeficiency virus type 1 replication by Z-100, an immunomodulator extracted from human-type tubercle bacilli, in macrophages. J Gen Virol. 2004;85:2603-13 pubmed
    ..These findings suggest that Z-100 might be a useful immunomodulator for control of HIV-1 infection. ..
  43. Gómez Icazbalceta G, Larralde C. [Linking Nef with the immunological and virological determinants of AIDS]. Rev Invest Clin. 2009;61:243-51 pubmed
    ..Under this approach, it is emphasized the role of Nef as immunomodulator and also as independent mediator of damage to the immune system. ..
  44. Agopian K, Wei B, Garcia J, Gabuzda D. CD4 and MHC-I downregulation are conserved in primary HIV-1 Nef alleles from brain and lymphoid tissues, but Pak2 activation is highly variable. Virology. 2007;358:119-35 pubmed
    ..However, little is known about tissue compartmentalization of nef genes and their functional characteristics in brain...
  45. Visco Comandini U, Yun Z, Paganelli R, Orlandi P, Salotti A, Johansson B, et al. HIV-1 nef mutations and clinical long-term nonprogression. A molecular epidemiology study. J Hum Virol. 1998;1:320-7 pubmed
    ..Nef gene defects appear uncommon in both Swedish and Italian LTNP, although the presence of a valine/isoleucine at position 11 is statistically associated with a lower probability to progress to disease. ..
  46. Park I, Myrick K, Sodroski J. Effects of vif mutations on cell-free infectivity and replication of simian immunodeficiency virus. J Acquir Immune Defic Syndr. 1994;7:1228-36 pubmed
    ..The effects of two different point mutations in vif were examined. One point mutant in vif reverted to the genetic sequence of the wild-type virus within 2 weeks.2 + ..
  47. Erdtmann L, Janvier K, Raposo G, Craig H, Benaroch P, Berlioz Torrent C, et al. Two independent regions of HIV-1 Nef are required for connection with the endocytic pathway through binding to the mu 1 chain of AP1 complex. Traffic. 2000;1:871-83 pubmed
    ..These data indicate that the recruitment by Nef of AP1 via binding to mu 1 participates in the connection of Nef with the endocytic pathway. ..
  48. Albrecht H. HIV pathogenesis and activation of CD4 cells. AIDS Clin Care. 2001;13:99 pubmed
    ..Selective upregulation of the transcription of nef and tat genes before integration into the human genome allows HIV to activate CD4 cells and increase viral replication. ..
  49. Hanna Z, Priceputu E, Hu C, Vincent P, Jolicoeur P. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice. Virology. 2006;346:40-52 pubmed
    ..Similarly, in HIV-1-infected individuals, loss of CD4 downregulation by Nef alleles may reflect their lower intrinsic pathogenicity, independently of their effects on virus replication. ..
  50. Park C, Lee D, Lee K, Lee C. Characterization and signature pattern analysis of Korean clade HIV-1 using nef gene sequences. J Microbiol. 2008;46:88-94 pubmed publisher
    ..The KCB signature amino acid residues were critical in identifying KCB from NKCB, since substitution of the NKCB sequences with KCB signature amino acids relocated them to the Koran clade, and vice versa. ..
  51. Dorival C, Brizzi F, Lelievre J, Sol Foulon N, Six E, Henry A, et al. HIV-1 Nef protein expression in human CD34+ progenitors impairs the differentiation of an early T/NK cell precursor. Virology. 2008;377:207-15 pubmed publisher
    ..Altogether, these data demonstrate that Nef interferes with the differentiation of a primitive lymphoid human precursor with a T/NK potential. ..
  52. Liang X, Fu T, Xie H, Emini E, Shiver J. Development of HIV-1 Nef vaccine components: immunogenicity study of Nef mutants lacking myristoylation and dileucine motif in mice. Vaccine. 2002;20:3413-21 pubmed
    ..These findings may have practical implications for developing HIV-1 Nef vaccine component. ..
  53. Tebit D, Zekeng L, Kaptue L, Gurtler L, Fackler O, Keppler O, et al. Construction and characterization of an HIV-1 group O infectious molecular clone and analysis of vpr- and nef-negative derivatives. Virology. 2004;326:329-39 pubmed
    ..5. Virus obtained from pCMO2.5 replicated with similar kinetics as the parental O-type isolate in both PBMC and MDM, making this proviral clone a valuable tool for further studies on functional characteristics of HIV-1 group O viruses. ..