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Journal of General Virology header logo Journal of General Virology

Volume 88, Issue 1

OTK18, a zinc-finger protein, regulates human immunodeficiency virus type 1 long terminal repeat through two distinct regulatory regions No Access

Abstract

It has previously been shown by our laboratory that OTK18, a human immunodeficiency virus (HIV)-inducible zinc-finger protein, reduces progeny-virion production in infected human macrophages. OTK18 antiviral activity is mediated through suppression of Tat-induced HIV-1 long terminal repeat (LTR) promoter activity. Through the use of LTR-scanning mutant vectors, the specific regions responsible for OTK18-mediated LTR suppression have been defined. Two different LTR regions were identified as potential OTK18-binding sites by an enhanced DNA–transcription factor ELISA system; the negative-regulatory element (NRE) at −255/−238 and the Ets-binding site (EBS) at −150/−139 in the LTR. In addition, deletion of the EBS in the LTR blocked OTK18-mediated LTR suppression. These data indicate that OTK18 suppresses LTR activity through two distinct regulatory elements. Spontaneous mutations in these regions might enable HIV-1 to escape from OTK18 antiretroviral activity in human macrophages.

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/content/journal/jgv/10.1099/vir.0.82066-0
2007-01-01
2025-12-06

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References

  1. Carlson K. A., Leisman G., Limoges J., Pohlman G. D., Horiba M., Buescher J., Gendelman H. E., Ikezu T. 2004a; Molecular characterization of a putative antiretroviral transcriptional factor, OTK18. J Immunol 172:381–391 [CrossRef]
     [Google Scholar]
  2. Carlson K. A., Limoges J., Pohlman G. D., Poluektova L. Y., Langford D., Masliah E., Ikezu T., Gendelman H. E. 2004b; OTK18 expression in brain mononuclear phagocytes parallels the severity of HIV-1 encephalitis. J Neuroimmunol 150:186–198 [CrossRef]
     [Google Scholar]
  3. Cicala C., Arthos J., Selig S. M., Dennis G. Jr, Hosack D. A., Van Ryk D., Spangler M. L., Steenbeke T. D., Khazanie P. other authors 2002; HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication. Proc Natl Acad Sci U S A 99:9380–9385 [CrossRef]
     [Google Scholar]
  4. De Arellano E. R., Soriano V., Holguin A. 2005; Genetic analysis of regulatory, promoter, and TAR regions of LTR sequences belonging to HIV type 1 non-B subtypes. AIDS Res Hum Retroviruses 21:949–954 [CrossRef]
     [Google Scholar]
  5. Estable M. C., Bell B., Merzouki A., Montaner J. S., O'Shaughnessy M. V., Sadowski I. J. 1996; Human immunodeficiency virus type 1 long terminal repeat variants from 42 patients representing all stages of infection display a wide range of sequence polymorphism and transcription activity. J Virol 70:4053–4062
     [Google Scholar]
  6. Galio L., Briquet S., Vaquero C. 1999; Real-time study of interactions between a composite DNA regulatory region (HIV-1 LTR NRE) and several transcription factors of nuclear extracts. Biochem Biophys Res Commun 264:6–13 [CrossRef]
     [Google Scholar]
  7. Garcia J. A., Wu F. K., Mitsuyasu R., Gaynor R. B. 1987; Interactions of cellular proteins involved in the transcriptional regulation of the human immunodeficiency virus. EMBO J 6:3761–3770
     [Google Scholar]
  8. Griffin G. E., Leung K., Folks T. M., Kunkel S., Nabel G. J. 1989; Activation of HIV gene expression during monocyte differentiation by induction of NF- κ B. Nature 339:70–73 [CrossRef]
     [Google Scholar]
  9. Hayes M. M., Lane B. R., King S. R., Markovitz D. M., Coffey M. J. 2002; Peroxisome proliferator-activated receptor γ agonists inhibit HIV-1 replication in macrophages by transcriptional and post-transcriptional effects. J Biol Chem 277:16913–16919 [CrossRef]
     [Google Scholar]
  10. Henderson A. J., Connor R. I., Calame K. L. 1996; C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines. Immunity 5:91–101 [CrossRef]
     [Google Scholar]
  11. Herchenroder O., Hahne J. C., Meyer W. K., Thiesen H. J., Schneider J. 1999; Repression of the human immunodeficiency virus type 1 promoter by the human KRAB domain results in inhibition of virus production. Biochim Biophys Acta 1445216–223 [CrossRef]
     [Google Scholar]
  12. Hoover T., Mikovits J., Court D., Liu Y. L., Kung H. F., Raziuddin. 1996; A nuclear matrix-specific factor that binds a specific segment of the negative regulatory element (NRE) of HIV-1 LTR and inhibits NF- κ B activity. Nucleic Acids Res 24:1895–1900 [CrossRef]
     [Google Scholar]
  13. Isalan M., Klug A., Choo Y. 2001; A rapid, generally applicable method to engineer zinc fingers illustrated by targeting the HIV-1 promoter. Nat Biotechnol 19:656–660 [CrossRef]
     [Google Scholar]
  14. Patarca R., Freeman G. J., Schwartz J., Singh R. P., Kong Q. T., Murphy E., Anderson Y., Sheng F. Y., Singh P. other authors 1988; rpt-1, an intracellular protein from helper/inducer T cells that regulates gene expression of interleukin 2 receptor and human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 85:2733–2737 [CrossRef]
     [Google Scholar]
  15. Pengue G., Caputo A., Rossi C., Barbanti-Brodano G., Lania L. 1995; Transcriptional silencing of human immunodeficiency virus type 1 long terminal repeat-driven gene expression by the Kruppel-associated box repressor domain targeted to the transactivating response element. J Virol 69:6577–6580
     [Google Scholar]
  16. Ray R. B., Srinivas R. V. 1997; Inhibition of human immunodeficiency virus type 1 replication by a cellular transcriptional factor MBP-1. J Cell Biochem 64:565–572 [CrossRef]
     [Google Scholar]
  17. Reynolds L., Ullman C., Moore M., Isalan M., West M. J., Clapham P., Klug A., Choo Y. 2003; Repression of the HIV-1 5′ LTR promoter and inhibition of HIV-1 replication by using engineered zinc-finger transcription factors. Proc Natl Acad Sci U S A 100:1615–1620 [CrossRef]
     [Google Scholar]
  18. Saito H., Fujiwara T., Takahashi E. I., Shin S., Okui K., Nakamura Y. 1996; Isolation and mapping of a novel human gene encoding a protein containing zinc-finger structures. Genomics 31:376–379 [CrossRef]
     [Google Scholar]
  19. Sawadogo M., Van Dyke M. W., Gregor P. D., Roeder R. G. 1988; Multiple forms of the human gene-specific transcription factor USF. I. Complete purification and identification of USF from HeLa cell nuclei. J Biol Chem 263:11985–11993
     [Google Scholar]
  20. Sieweke M. H., Tekotte H., Jarosch U., Graf T. 1998; Cooperative interaction of ets-1 with USF-1 required for HIV-1 enhancer activity in T cells. EMBO J 17:1728–1739 [CrossRef]
     [Google Scholar]
  21. Subler M. A., Martin D. W., Deb S. 1994; Activation of the human immunodeficiency virus type 1 long terminal repeat by transforming mutants of human p53. J Virol 68:103–110
     [Google Scholar]
  22. Subramani S., Mulligan R., Berg P. 1981; Expression of the mouse dihydrofolate reductase complementary deoxyribonucleic acid in simian virus 40 vectors. Mol Cell Biol 1:854–864
     [Google Scholar]
  23. Tesmer V. M., Rajadhyaksha A., Babin J., Bina M. 1993; NF-IL6-mediated transcriptional activation of the long terminal repeat of the human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 90:7298–7302 [CrossRef]
     [Google Scholar]
  24. Weiden M., Tanaka N., Qiao Y., Zhao B. Y., Honda Y., Nakata K., Canova A., Levy D. E., Rom W. N., Pine R. 2000; Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: modulation of interferon response and CCAAT/enhancer binding protein β expression. J Immunol 165:2028–2039 [CrossRef]
     [Google Scholar]
  25. Wu H., Yang W. P., Barbas C. F. III 1995; Building zinc fingers by selection: toward a therapeutic application. Proc Natl Acad Sci U S A 92:344–348 [CrossRef]
     [Google Scholar]
  26. Yang Z., Engel J. D. 1993; Human T cell transcription factor GATA-3 stimulates HIV-1 expression. Nucleic Acids Res 21:2831–2836 [CrossRef]
     [Google Scholar]
  27. Zeichner S. L., Kim J. Y., Alwine J. C. 1991; Linker-scanning mutational analysis of the transcriptional activity of the human immunodeficiency virus type 1 long terminal repeat. J Virol 65:2436–2444
     [Google Scholar]
  28. Zhang J. H., Chung T. D., Oldenburg K. R. 1999; A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4:67–73 [CrossRef]
     [Google Scholar]
/content/journal/jgv/10.1099/vir.0.82066-0
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OTK18, a zinc-finger protein, regulates human immunodeficiency virus type 1 long terminal repeat through two distinct regulatory regions
J. Gen. Virol. 88, 236 (2007); https://doi.org/10.1099/vir.0.82066-0
/content/journal/jgv/10.1099/vir.0.82066-0
/content/journal/jgv/10.1099/vir.0.82066-0
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