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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 May 15;90(10):4674–4678. doi: 10.1073/pnas.90.10.4674

Gö 6976, a selective inhibitor of protein kinase C, is a potent antagonist of human immunodeficiency virus 1 induction from latent/low-level-producing reservoir cells in vitro.

K A Qatsha 1, C Rudolph 1, D Marmé 1, C Schächtele 1, W S May 1
PMCID: PMC46575  PMID: 7685108

Abstract

Human immunodeficiency virus (HIV-1) infection is followed by a period of latency or a low-level-persistent (LLP) state that results in an asymptomatic infection of the host. Productive viral expression may be triggered by a variety of activators including mitogens, antigens, and cytokines. Protein kinase C (PKC) has been shown to be important in the intracellular cascade of signals induced by such activators. With U1 and ACH-2 cell lines representative of an HIV-1 postintegration state, the effect of Gö 6976, a synthetic inhibitor of PKC was tested. Gö 6976 is a nonglycosidic indolocarbazole found to potently inhibit HIV-1 induction by Bryostatin 1, tumor necrosis factor alpha, and interleukin 6. Gö 6976 effectively blocks viral transcription induced by Bryostatin 1 or tumor necrosis factor alpha that leads to the inhibition of intracellular viral protein synthesis and viral shedding. Gö 6976 also blocks interleukin 6-mediated posttranscriptional induction of viral proteins. The IC50 of Gö 6976 shows a 12- to 60-fold more potent effect than for H-7, another PKC inhibitor with a similar mechanism. The inhibitory effect is reduced when Gö 6976 is not added before or within 1 hr of induction by the potent PKC activator Bryostatin 1. However, U1 cells can be grown for long periods in a nontoxic concentration of Gö 6976 (300 nM), which confers virtual inhibition of HIV-1 induction without the development of resistance. Results indicate that inhibition of HIV-1 proviral induction from latent/low-level-producing infectious states with potent PKC inhibitors like Gö 6976 may represent an additional and promising antiviral approach.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baeuerle P. A., Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. doi: 10.1126/science.3140380. [DOI] [PubMed] [Google Scholar]
  2. Bednarik D. P., Folks T. M. Mechanisms of HIV-1 latency. AIDS. 1992 Jan;6(1):3–16. doi: 10.1097/00002030-199201000-00001. [DOI] [PubMed] [Google Scholar]
  3. Bednarik D. P., Mosca J. D., Raj N. B., Pitha P. M. Inhibition of human immunodeficiency virus (HIV) replication by HIV-trans-activated alpha 2-interferon. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4958–4962. doi: 10.1073/pnas.86.13.4958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Duh E. J., Maury W. J., Folks T. M., Fauci A. S., Rabson A. B. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974–5978. doi: 10.1073/pnas.86.15.5974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fields A. P., Bednarik D. P., Hess A., May W. S. Human immunodeficiency virus induces phosphorylation of its cell surface receptor. Nature. 1988 May 19;333(6170):278–280. doi: 10.1038/333278a0. [DOI] [PubMed] [Google Scholar]
  7. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  8. Folks T. M., Justement J., Kinter A., Schnittman S., Orenstein J., Poli G., Fauci A. S. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. J Immunol. 1988 Feb 15;140(4):1117–1122. [PubMed] [Google Scholar]
  9. Folks T., Benn S., Rabson A., Theodore T., Hoggan M. D., Martin M., Lightfoote M., Sell K. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4539–4543. doi: 10.1073/pnas.82.13.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Garcia-Blanco M. A., Cullen B. R. Molecular basis of latency in pathogenic human viruses. Science. 1991 Nov 8;254(5033):815–820. doi: 10.1126/science.1658933. [DOI] [PubMed] [Google Scholar]
  11. Goff S., Traktman P., Baltimore D. Isolation and properties of Moloney murine leukemia virus mutants: use of a rapid assay for release of virion reverse transcriptase. J Virol. 1981 Apr;38(1):239–248. doi: 10.1128/jvi.38.1.239-248.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hathaway D. R., Haeberle J. R. Selective purification of the 20,000-Da light chains of smooth muscle myosin. Anal Biochem. 1983 Nov;135(1):37–43. doi: 10.1016/0003-2697(83)90726-1. [DOI] [PubMed] [Google Scholar]
  13. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  14. Inagaki M., Watanabe M., Hidaka H. N-(2-Aminoethyl)-5-isoquinolinesulfonamide, a newly synthesized protein kinase inhibitor, functions as a ligand in affinity chromatography. Purification of Ca2+-activated, phospholipid-dependent and other protein kinases. J Biol Chem. 1985 Mar 10;260(5):2922–2925. [PubMed] [Google Scholar]
  15. Jakobovits A., Rosenthal A., Capon D. J. Trans-activation of HIV-1 LTR-directed gene expression by tat requires protein kinase C. EMBO J. 1990 Apr;9(4):1165–1170. doi: 10.1002/j.1460-2075.1990.tb08223.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kinter A. L., Poli G., Maury W., Folks T. M., Fauci A. S. Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells. J Virol. 1990 Sep;64(9):4306–4312. doi: 10.1128/jvi.64.9.4306-4312.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kraft A. S., Baker V. V., May W. S. Bryostatin induces changes in protein kinase C location and activity without altering c-myc gene expression in human promyelocytic leukemia cells (HL-60). Oncogene. 1987 May;1(2):111–118. [PubMed] [Google Scholar]
  18. Liu A. Y., Miskovsky E. P., Stanhope P. E., Siliciano R. F. Production of transmembrane and secreted forms of tumor necrosis factor (TNF)-alpha by HIV-1-specific CD4+ cytolytic T lymphocyte clones. Evidence for a TNF-alpha-independent cytolytic mechanism. J Immunol. 1992 Jun 15;148(12):3789–3798. [PubMed] [Google Scholar]
  19. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  20. Ngai P. K., Carruthers C. A., Walsh M. P. Isolation of the native form of chicken gizzard myosin light-chain kinase. Biochem J. 1984 Mar 15;218(3):863–870. doi: 10.1042/bj2180863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ou C. Y., Kwok S., Mitchell S. W., Mack D. H., Sninsky J. J., Krebs J. W., Feorino P., Warfield D., Schochetman G. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science. 1988 Jan 15;239(4837):295–297. doi: 10.1126/science.3336784. [DOI] [PubMed] [Google Scholar]
  23. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms. J Exp Med. 1990 Jul 1;172(1):151–158. doi: 10.1084/jem.172.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  25. Schächtele C., Wagner B., Rudolph C. Effect of Ca2+ entry blockers on myosin light-chain kinase and protein kinase C. Eur J Pharmacol. 1989 Apr 12;163(1):151–155. doi: 10.1016/0014-2999(89)90410-x. [DOI] [PubMed] [Google Scholar]
  26. Schütze S., Nottrott S., Pfizenmaier K., Krönke M. Tumor necrosis factor signal transduction. Cell-type-specific activation and translocation of protein kinase C. J Immunol. 1990 Apr 1;144(7):2604–2608. [PubMed] [Google Scholar]
  27. Schütze S., Potthoff K., Machleidt T., Berkovic D., Wiegmann K., Krönke M. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown. Cell. 1992 Nov 27;71(5):765–776. doi: 10.1016/0092-8674(92)90553-o. [DOI] [PubMed] [Google Scholar]
  28. Steffens U., Bessler W., Hauschild S. B cell activation by synthetic lipopeptide analogues of bacterial lipoprotein bypassing phosphatidylinositol metabolism and proteinkinase C translocation. Mol Immunol. 1989 Sep;26(9):897–904. doi: 10.1016/0161-5890(89)90146-6. [DOI] [PubMed] [Google Scholar]
  29. Tamaoki T., Nomoto H., Takahashi I., Kato Y., Morimoto M., Tomita F. Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase. Biochem Biophys Res Commun. 1986 Mar 13;135(2):397–402. doi: 10.1016/0006-291x(86)90008-2. [DOI] [PubMed] [Google Scholar]
  30. Vlach J., Pitha P. M. Activation of human immunodeficiency virus type 1 provirus in T-cells and macrophages is associated with induction of inducer-specific NF-kappa B binding proteins. Virology. 1992 Mar;187(1):63–72. doi: 10.1016/0042-6822(92)90295-z. [DOI] [PubMed] [Google Scholar]
  31. Walter U., Miller P., Wilson F., Menkes D., Greengard P. Immunological distinction between guanosine 3':5'-monophosphate-dependent and adenosine 3':5'-monophosphate-dependent protein kinases. J Biol Chem. 1980 Apr 25;255(8):3757–3762. [PubMed] [Google Scholar]

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