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Gene Review

tat  -  p14

Human immunodeficiency virus 1

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Disease relevance of tat

  • Each encodes a protein able to trans-activate transcription from the homologous viral long terminal repeat (tat in HIV, tax in HTLV), although these proteins act by different mechanisms and do not appear to be interchangeable [1].
  • Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans [2].
  • In a two-step virus rescue protocol, during which introns are removed from the DNA fragments inserted into pLXSN, these plasmids were used to establish amphotropic retrovirus vector producer lines for the transfer of tat (LtatSN), rev (LrevSN), and nef (LnefSN) [3].
  • Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions [4].
  • Facilitation of glutamate-triggered calcium flux by Tat was prevented by inhibitors of ADP-ribosylation of G(i)/G(o) proteins (pertussis toxin), protein kinase C (H7 and bisindolymide), and IP3-mediated calcium release (xestospongin C), but was not prevented by an activator of G(s) (cholera toxin) or an inhibitor of protein kinase A (H89) [5].

Psychiatry related information on tat

  • This study illustrates a novel role for HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia [6].
  • Unlike our earlier studies of tat and env, nef evolution was not affected by morphine abuse or by rapid disease progression [7].
  • Gene chromosomal organization and expression in cultured human neurons exposed to cocaine and HIV-1 proteins gp120 and tat: drug abuse and NeuroAIDS [8].
  • In this study, we tested for antibody reactivities against gp120 and gp41-derived peptides, recombinant gp160, gp41 and tat in HIV-positive sera under antiretroviral therapy (ART) and determined their neutralization capacity [9].

High impact information on tat

  • In this issue of Cell, take an integrated computational-experimental approach to study the Tat transactivation feedback loop of HIV-1 [10].
  • Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity [11].
  • HIV-1 Tat transactivation is vital for completion of the viral life cycle and has been implicated in determining proviral latency [11].
  • Low GFP/Tat expression was found to generate bifurcating phenotypes with clonal populations derived from single proviral integrations simultaneously exhibiting very high and near zero GFP expression [11].
  • We present an extensive experimental/computational study of an HIV-1 model vector (LTR-GFP-IRES-Tat) and show that stochastic fluctuations in Tat influence the viral latency decision [11].

Chemical compound and disease context of tat

  • HIV-1 Tat raises an adjuvant-free humoral immune response controlled by its core region and its ability to form cysteine-mediated oligomers [12].
  • By utilizing HIV-1 Tat, as well as ProboroPro, a potent and specific boronic acid analog inhibitor of DP IV, we show here that blocking DP IV partially inactivates Ag and anti-CD3-mediated T cell proliferation [13].
  • HIV-1 Tat increases endothelial solute permeability through tyrosine kinase and mitogen-activated protein kinase-dependent pathways [14].
  • Among them, the HIV-1 regulatory protein Tat, which was shown to have neurotoxic activity, is able to promote some proinflammatory functions of microglia [15].
  • Together, these findings suggest that NMDA receptors play an important role in Tat neurotoxicity and the mechanisms identified may provide additional therapeutic targets for the treatment of HIV-1 associated dementia [5].

Biological context of tat

  • The data also suggest that sor influences virus replication at a novel, post-translational stage and that its action is independent of the regulatory genes tat and trs [16].
  • Eight coding regions designated gag, pol, env, sor, R, tat, art/trs, and 3' orf have been identified in the genome of the human immunodeficiency virus type 1 (HIV-1) [17].
  • Genomic RNA and DNA from productively infected H9 cells were independently extracted and amplified in reactions with and without reverse transcriptase respectively using primer pairs to the gag, env, tat and nef regions of the viral genome in the same reaction mixture [18].
  • The efficacy of a combination of DNA plasmids encoding the nef, rev, and tat HIV-1 regulatory genes in inducing cellular immune responses was analyzed in asymptomatic HIV-1-infected patients [19].
  • Following transfection of wild-type and mutant proviral constructs, we can specifically detect unspliced RNA and distinguish between the spliced tat-rev and nef mRNAs, which are not resolved by standard RNA analyses [20].

Anatomical context of tat


Associations of tat with chemical compounds

  • Similar to Nef action, activation of integrin receptors recruited Eed to the plasma membrane, also leading to enhanced Tat/Nef-mediated transcription [24].
  • In particular, a Tat dimer formed by the oxidation of two cysteine residues, at position 34 only, raises an adjuvant-free antibody response that is comparable with that observed with the wild-type protein [12].
  • In wild type cells, Tat uptake is competitively inhibited by soluble heparin and by treatment with glycosaminoglycan lyases specifically degrading HS chains [2].
  • To identify the cellular gene target for Tat, we performed gene expression profile analysis and found that Tat up-regulates the expression of the OGG1 (8-oxoguanine-DNA glycosylase-1) gene, which encodes an enzyme responsible for repairing the oxidatively damaged guanosine, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) [25].
  • These data demonstrate that Tat increases endothelial albumin permeability in vitro through tyrosine kinase and MAP kinase, but not protein kinase G pathways [14].

Physical interactions of tat


Regulatory relationships of tat

  • 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 [24].
  • Nuclear accumulation of Rev in astrocytes was restored by blocking export of Rev. The trans activation capacity and nuclear localization of Tat were not affected in astrocytes [28].
  • This group contains nine bicistronic mRNAs producing Env and Vpu and three mRNAs expressing only the first exon of tat [29].
  • The data indicate that a specific residue in the cyclin T proteins is required for their in vitro interaction with Tat and their ability to stimulate in vivo tat-activation [30].

Other interactions of tat

  • Here, we report that HIV infection leads to selective transcription of the nef and tat genes before integration [31].
  • Tat and rev appear to be prototypes of novel eukaryotic regulatory proteins [32].
  • DNA sequence analysis of HIV-1 derived regions of SHIV(KU-2MC4) revealed 2, 1, 2, and 18 predicted amino acid substitutions in the Tat, Rev, Vpu, and Env proteins, respectively, when compared to SHIV-4 [33].
  • We have mapped the activity of the enhancer to two independent domains encompassing nucleotides 4079-4342 (end of the pol gene) and nucleotides 4781-6026 (vif gene and first coding exon of tat) [34].
  • In this study, we further defined the element to a 20-nucleotide (nt) region which spans the C-terminal vpr and N-terminal tat coding sequences [35].

Analytical, diagnostic and therapeutic context of tat

  • This property can be exploited for the cellular delivery of heterologous proteins fused to Tat both in cell culture and in living animals [2].
  • Cells genetically defective in the biosynthesis of fully sulfated HS are selectively impaired in the internalization of recombinant Tat fused to the green fluorescent protein, as evaluated by both flow cytometry and functional assays [2].
  • Trans-dominant mutants of human immunodeficiency virus type 1 (HIV-1) Tat and Rev are attractive candidates for use in gene therapy in the treatment of HIV-1 infections because both are essential for viral replication [36].
  • Interestingly, this time corresponded to that required for the uptake and nuclear localization of recombinant Tat protein, as demonstrated by electron microscope immunocytochemistry experiments with anti-Tat mAb [37].
  • When microglial cultures obtained from neonatal rats were treated with Tat (> or = 100 ng/ml), whole-cell recording showed the appearance of a large outwardly rectifying current (OR) virtually absent in untreated control cells [15].


  1. Functional replacement of the HIV-1 rev protein by the HTLV-1 rex protein. Rimsky, L., Hauber, J., Dukovich, M., Malim, M.H., Langlois, A., Cullen, B.R., Greene, W.C. Nature (1988) [Pubmed]
  2. Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. Tyagi, M., Rusnati, M., Presta, M., Giacca, M. J. Biol. Chem. (2001) [Pubmed]
  3. Retrovirus vector-mediated transfer of functional HIV-1 regulatory genes. Garcia, J.V., Miller, A.D. AIDS Res. Hum. Retroviruses (1994) [Pubmed]
  4. Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions. Taraboletti, G., Benelli, R., Borsotti, P., Rusnati, M., Presta, M., Giavazzi, R., Ruco, L., Albini, A. J. Pathol. (1999) [Pubmed]
  5. HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. Haughey, N.J., Nath, A., Mattson, M.P., Slevin, J.T., Geiger, J.D. J. Neurochem. (2001) [Pubmed]
  6. Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. Liu, X., Jana, M., Dasgupta, S., Koka, S., He, J., Wood, C., Pahan, K. J. Biol. Chem. (2002) [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. Gene chromosomal organization and expression in cultured human neurons exposed to cocaine and HIV-1 proteins gp120 and tat: drug abuse and NeuroAIDS. Shapshak, P., Duncan, R., Nath, A., Turchan, J., Pandjassarame, K., Rodriguez, H., Duran, E.M., Ziegler, F., Amaro, E., Lewis, A., Rodriguez, A., Minagar, A., Davis, W., Seth, R., Elkomy, F.F., Chiappelli, F., Kazic, T. Front. Biosci. (2006) [Pubmed]
  9. Changes in HIV-specific antibody responses and neutralization titers in patients under ART. Falkensammer, B., Freissmuth, D., H??bner, L., Speth, C., Dierich, M.P., Stoiber, H. Front. Biosci. (2007) [Pubmed]
  10. And the noise played on: stochastic gene expression and HIV-1 infection. Blake, W.J., Collins, J.J. Cell (2005) [Pubmed]
  11. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Weinberger, L.S., Burnett, J.C., Toettcher, J.E., Arkin, A.P., Schaffer, D.V. Cell (2005) [Pubmed]
  12. HIV-1 Tat raises an adjuvant-free humoral immune response controlled by its core region and its ability to form cysteine-mediated oligomers. Kittiworakarn, J., Lecoq, A., Moine, G., Thai, R., Lajeunesse, E., Drevet, P., Vidaud, C., Ménez, A., Léonetti, M. J. Biol. Chem. (2006) [Pubmed]
  13. Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness. Subramanyam, M., Gutheil, W.G., Bachovchin, W.W., Huber, B.T. J. Immunol. (1993) [Pubmed]
  14. HIV-1 Tat increases endothelial solute permeability through tyrosine kinase and mitogen-activated protein kinase-dependent pathways. Oshima, T., Flores, S.C., Vaitaitis, G., Coe, L.L., Joh, T., Park, J.H., Zhu, Y., Alexander, B., Alexander, J.S. AIDS (2000) [Pubmed]
  15. Altered outward-rectifying K(+) current reveals microglial activation induced by HIV-1 Tat protein. Visentin, S., Renzi, M., Levi, G. Glia (2001) [Pubmed]
  16. The sor gene of HIV-1 is required for efficient virus transmission in vitro. Fisher, A.G., Ensoli, B., Ivanoff, L., Chamberlain, M., Petteway, S., Ratner, L., Gallo, R.C., Wong-Staal, F. Science (1987) [Pubmed]
  17. Human immunodeficiency virus type 1 has an additional coding sequence in the central region of the genome. Matsuda, Z., Chou, M.J., Matsuda, M., Huang, J.H., Chen, Y.M., Redfield, R., Mayer, K., Essex, M., Lee, T.H. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  18. Co-amplification of multiple regions of the HIV-1 genome by the polymerase chain reaction: potential use in multiple diagnosis. Hewlett, I.K., Ruta, M., Cristiano, K., Hawthorne, C.A., Epstein, J.S. Oncogene (1989) [Pubmed]
  19. Gene combination raises broad human immunodeficiency virus-specific cytotoxicity. Calarota, S.A., Kjerrström, A., Islam, K.B., Wahren, B. Hum. Gene Ther. (2001) [Pubmed]
  20. Analysis of rev gene function on human immunodeficiency virus type 1 replication in lymphoid cells by using a quantitative polymerase chain reaction method. Arrigo, S.J., Weitsman, S., Rosenblatt, J.D., Chen, I.S. J. Virol. (1989) [Pubmed]
  21. 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]
  22. Constitutive expression of human immunodeficiency virus type 1 tat gene inhibits interleukin 2 and interleukin 2 receptor expression in a human CD4+ T lymphoid (H9) cell line. Puri, R.K., Leland, P., Aggarwal, B.B. AIDS Res. Hum. Retroviruses (1995) [Pubmed]
  23. Differential expression of cytokine genes in HIV-1 tat transfected T and B cell lines. Sharma, V., Knobloch, T.J., Benjamin, D. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  24. 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]
  25. Induction of OGG1 gene expression by HIV-1 Tat. Imai, K., Nakata, K., Kawai, K., Hamano, T., Mei, N., Kasai, H., Okamoto, T. J. Biol. Chem. (2005) [Pubmed]
  26. The VP16 transcription activation domain is functional when targeted to a promoter-proximal RNA sequence. Tiley, L.S., Madore, S.J., Malim, M.H., Cullen, B.R. Genes Dev. (1992) [Pubmed]
  27. 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]
  28. Diminished rev-mediated stimulation of human immunodeficiency virus type 1 protein synthesis is a hallmark of human astrocytes. Ludwig, E., Silberstein, F.C., van Empel, J., Erfle, V., Neumann, M., Brack-Werner, R. J. Virol. (1999) [Pubmed]
  29. Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple bicistronic mRNAs. Schwartz, S., Felber, B.K., Fenyö, E.M., Pavlakis, G.N. J. Virol. (1990) [Pubmed]
  30. Role of the human and murine cyclin T proteins in regulating HIV-1 tat-activation. Kwak, Y.T., Ivanov, D., Guo, J., Nee, E., Gaynor, R.B. J. Mol. Biol. (1999) [Pubmed]
  31. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Wu, Y., Marsh, J.W. Science (2001) [Pubmed]
  32. Molecular biology of the human immunodeficiency virus type 1. Haseltine, W.A. FASEB J. (1991) [Pubmed]
  33. Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques. Liu, Z.Q., Muhkerjee, S., Sahni, M., McCormick-Davis, C., Leung, K., Li, Z., Gattone, V.H., Tian, C., Doms, R.W., Hoffman, T.L., Raghavan, R., Narayan, O., Stephens, E.B. Virology (1999) [Pubmed]
  34. Identification and characterization of an enhancer in the coding region of the genome of human immunodeficiency virus type 1. Verdin, E., Becker, N., Bex, F., Droogmans, L., Burny, A. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  35. Presence of exon splicing silencers within human immunodeficiency virus type 1 tat exon 2 and tat-rev exon 3: evidence for inhibition mediated by cellular factors. Amendt, B.A., Si, Z.H., Stoltzfus, C.M. Mol. Cell. Biol. (1995) [Pubmed]
  36. The development and testing of retroviral vectors expressing trans-dominant mutants of HIV-1 proteins to confer anti-HIV-1 resistance. Liem, S.E., Ramezani, A., Li, X., Joshi, S. Hum. Gene Ther. (1993) [Pubmed]
  37. Exogenous human immunodeficiency virus type-1 Tat protein selectively stimulates a phosphatidylinositol-specific phospholipase C nuclear pathway in the Jurkat T cell line. Zauli, G., Previati, M., Caramelli, E., Bassini, A., Falcieri, E., Gibellini, D., Bertolaso, L., Bosco, D., Robuffo, I., Capitani, S. Eur. J. Immunol. (1995) [Pubmed]
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