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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
. 1994 Jun 21;91(13):6012–6016. doi: 10.1073/pnas.91.13.6012

RNase inhibition of human immunodeficiency virus infection of H9 cells.

R J Youle 1, Y N Wu 1, S M Mikulski 1, K Shogen 1, R S Hamilton 1, D Newton 1, G D'Alessio 1, M Gravell 1
PMCID: PMC44127  PMID: 8016107

Abstract

Onconase and bovine seminal RNase, two members of the RNase A superfamily, inhibit human immunodeficiency virus type 1 replication in H9 leukemia cells 90-99.9% over a 4-day incubation at concentrations not toxic to uninfected H9 cells. Two other members of the same protein family, bovine pancreatic RNase A and human eosinophil-derived neurotoxin, have no detectable antiviral activity, demonstrating a strikingly selective antiviral activity among homologous ribonucleases. The antiviral RNases do not appear to affect viral particles directly but inhibit replication in host cell cultures. Onconase, already in clinical trials for cancer therapy, and bovine seminal RNase have potential as antiviral therapeutics.

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Selected References

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  1. Ardelt W., Mikulski S. M., Shogen K. Amino acid sequence of an anti-tumor protein from Rana pipiens oocytes and early embryos. Homology to pancreatic ribonucleases. J Biol Chem. 1991 Jan 5;266(1):245–251. [PubMed] [Google Scholar]
  2. Blackburn P., Gavilanes J. G. The role of lysine-41 of ribonuclease A in the interaction with RNase inhibitor from human placenta. J Biol Chem. 1980 Nov 25;255(22):10959–10965. [PubMed] [Google Scholar]
  3. Byers V. S., Levin A. S., Waites L. A., Starrett B. A., Mayer R. A., Clegg J. A., Price M. R., Robins R. A., Delaney M., Baldwin R. W. A phase I/II study of trichosanthin treatment of HIV disease. AIDS. 1990 Dec;4(12):1189–1196. doi: 10.1097/00002030-199012000-00002. [DOI] [PubMed] [Google Scholar]
  4. Chaudhary V. K., Mizukami T., Fuerst T. R., FitzGerald D. J., Moss B., Pastan I., Berger E. A. Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas exotoxin hybrid protein. Nature. 1988 Sep 22;335(6188):369–372. doi: 10.1038/335369a0. [DOI] [PubMed] [Google Scholar]
  5. D'Alessio G., Di Donato A., Parente A., Piccoli R. Seminal RNase: a unique member of the ribonuclease superfamily. Trends Biochem Sci. 1991 Mar;16(3):104–106. doi: 10.1016/0968-0004(91)90042-t. [DOI] [PubMed] [Google Scholar]
  6. D'Alessio G., Floridi A., De Prisco R., Pignero A., Leone E. [Bull semen ribonucleases. 1. Purification and physico-chemical properties of the major component]. Eur J Biochem. 1972 Mar 27;26(2):153–161. doi: 10.1111/j.1432-1033.1972.tb01751.x. [DOI] [PubMed] [Google Scholar]
  7. D'Alessio G. New and cryptic biological messages from RNases. Trends Cell Biol. 1993 Apr;3(4):106–109. doi: 10.1016/0962-8924(93)90166-x. [DOI] [PubMed] [Google Scholar]
  8. Endo Y., Tsurugi K., Lambert J. M. The site of action of six different ribosome-inactivating proteins from plants on eukaryotic ribosomes: the RNA N-glycosidase activity of the proteins. Biochem Biophys Res Commun. 1988 Feb 15;150(3):1032–1036. doi: 10.1016/0006-291x(88)90733-4. [DOI] [PubMed] [Google Scholar]
  9. Fernández-Puentes C., Carrasco L. Viral infection permeabilizes mammalian cells to protein toxins. Cell. 1980 Jul;20(3):769–775. doi: 10.1016/0092-8674(80)90323-2. [DOI] [PubMed] [Google Scholar]
  10. FitzGerald D. J., Padmanabhan R., Pastan I., Willingham M. C. Adenovirus-induced release of epidermal growth factor and pseudomonas toxin into the cytosol of KB cells during receptor-mediated endocytosis. Cell. 1983 Feb;32(2):607–617. doi: 10.1016/0092-8674(83)90480-4. [DOI] [PubMed] [Google Scholar]
  11. Gleich G. J., Adolphson C. R. The eosinophilic leukocyte: structure and function. Adv Immunol. 1986;39:177–253. doi: 10.1016/s0065-2776(08)60351-x. [DOI] [PubMed] [Google Scholar]
  12. Harthoorn A. M., van der Walt K., Young E. Possible therapy for capture myopathy in captured wild animals. Nature. 1974 Feb 22;247(5442):577–577. doi: 10.1038/247577a0. [DOI] [PubMed] [Google Scholar]
  13. Irvin J. D., Aron G. M. Chemical modifications of pokeweed antiviral protein: effects upon ribosome inactivation, antiviral activity and cytotoxicity. FEBS Lett. 1982 Nov 1;148(1):127–130. doi: 10.1016/0014-5793(82)81257-x. [DOI] [PubMed] [Google Scholar]
  14. Irvin J. D. Purification and partial characterization of the antiviral protein from Phytolacca americana which inhibits eukaryotic protein synthesis. Arch Biochem Biophys. 1975 Aug;169(2):522–528. doi: 10.1016/0003-9861(75)90195-2. [DOI] [PubMed] [Google Scholar]
  15. Kahn J. O., Kaplan L. D., Gambertoglio J. G., Bredesen D., Arri C. J., Turin L., Kibort T., Williams R. L., Lifson J. D., Volberding P. A. The safety and pharmacokinetics of GLQ223 in subjects with AIDS and AIDS-related complex: a phase I study. AIDS. 1990 Dec;4(12):1197–1204. doi: 10.1097/00002030-199012000-00003. [DOI] [PubMed] [Google Scholar]
  16. Kim Y. W., Fung M. S., Sun N. C., Sun C. R., Chang N. T., Chang T. W. Immunoconjugates that neutralize HIV virions kill T cells infected with diverse strains of HIV-1. J Immunol. 1990 Feb 15;144(4):1257–1262. [PubMed] [Google Scholar]
  17. Lee-Huang S., Huang P. L., Kung H. F., Li B. Q., Huang P. L., Huang P., Huang H. I., Chen H. C. TAP 29: an anti-human immunodeficiency virus protein from Trichosanthes kirilowii that is nontoxic to intact cells. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6570–6574. doi: 10.1073/pnas.88.15.6570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lee-Huang S., Huang P. L., Nara P. L., Chen H. C., Kung H. F., Huang P., Huang H. I., Huang P. L. MAP 30: a new inhibitor of HIV-1 infection and replication. FEBS Lett. 1990 Oct 15;272(1-2):12–18. doi: 10.1016/0014-5793(90)80438-o. [DOI] [PubMed] [Google Scholar]
  19. Lee T., Crowell M., Shearer M. H., Aron G. M., Irvin J. D. Poliovirus-mediated entry of pokeweed antiviral protein. Antimicrob Agents Chemother. 1990 Oct;34(10):2034–2037. doi: 10.1128/aac.34.10.2034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lodge J. K., Kaniewski W. K., Tumer N. E. Broad-spectrum virus resistance in transgenic plants expressing pokeweed antiviral protein. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7089–7093. doi: 10.1073/pnas.90.15.7089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mazzarella L., Capasso S., Demasi D., Di Lorenzo G., Mattia C. A., Zagari A. Bovine seminal ribonuclease: structure at 1.9 A resolution. Acta Crystallogr D Biol Crystallogr. 1993 Jul 1;49(Pt 4):389–402. doi: 10.1107/S0907444993003403. [DOI] [PubMed] [Google Scholar]
  22. McGrath M. S., Hwang K. M., Caldwell S. E., Gaston I., Luk K. C., Wu P., Ng V. L., Crowe S., Daniels J., Marsh J. GLQ223: an inhibitor of human immunodeficiency virus replication in acutely and chronically infected cells of lymphocyte and mononuclear phagocyte lineage. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2844–2848. doi: 10.1073/pnas.86.8.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mikulski S. M., Ardelt W., Shogen K., Bernstein E. H., Menduke H. Striking increase of survival of mice bearing M109 Madison carcinoma treated with a novel protein from amphibian embryos. J Natl Cancer Inst. 1990 Jan 17;82(2):151–153. doi: 10.1093/jnci/82.2.151-a. [DOI] [PubMed] [Google Scholar]
  24. Mikulski S. M., Viera A., Ardelt W., Menduke H., Shogen K. Tamoxifen and trifluoroperazine (Stelazine) potentiate cytostatic/cytotoxic effects of P-30 protein, a novel protein possessing anti-tumor activity. Cell Tissue Kinet. 1990 May;23(3):237–246. doi: 10.1111/j.1365-2184.1990.tb01119.x. [DOI] [PubMed] [Google Scholar]
  25. Mosimann S. C., Johns K. L., Ardelt W., Mikulski S. M., Shogen K., James M. N. Comparative molecular modeling and crystallization of P-30 protein: a novel antitumor protein of Rana pipiens oocytes and early embryos. Proteins. 1992 Nov;14(3):392–400. doi: 10.1002/prot.340140308. [DOI] [PubMed] [Google Scholar]
  26. Murthy B. S., Sirdeshmukh R. Sensitivity of monomeric and dimeric forms of bovine seminal ribonuclease to human placental ribonuclease inhibitor. Biochem J. 1992 Jan 15;281(Pt 2):343–348. doi: 10.1042/bj2810343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Newton D. L., Ilercil O., Laske D. W., Oldfield E., Rybak S. M., Youle R. J. Cytotoxic ribonuclease chimeras. Targeted tumoricidal activity in vitro and in vivo. J Biol Chem. 1992 Sep 25;267(27):19572–19578. [PubMed] [Google Scholar]
  28. Newton D. L., Walbridge S., Mikulski S. M., Ardelt W., Shogen K., Ackerman S. J., Rybak S. M., Youle R. J. Toxicity of an antitumor ribonuclease to Purkinje neurons. J Neurosci. 1994 Feb;14(2):538–544. doi: 10.1523/JNEUROSCI.14-02-00538.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pincus S. H., Wehrly K., Chesebro B. Treatment of HIV tissue culture infection with monoclonal antibody-ricin A chain conjugates. J Immunol. 1989 May 1;142(9):3070–3075. [PubMed] [Google Scholar]
  30. Rybak S. M., Saxena S. K., Ackerman E. J., Youle R. J. Cytotoxic potential of ribonuclease and ribonuclease hybrid proteins. J Biol Chem. 1991 Nov 5;266(31):21202–21207. [PubMed] [Google Scholar]
  31. Saxena S. K., Rybak S. M., Winkler G., Meade H. M., McGray P., Youle R. J., Ackerman E. J. Comparison of RNases and toxins upon injection into Xenopus oocytes. J Biol Chem. 1991 Nov 5;266(31):21208–21214. [PubMed] [Google Scholar]
  32. Sorrentino S., Glitz D. G., Hamann K. J., Loegering D. A., Checkel J. L., Gleich G. J. Eosinophil-derived neurotoxin and human liver ribonuclease. Identity of structure and linkage of neurotoxicity to nuclease activity. J Biol Chem. 1992 Jul 25;267(21):14859–14865. [PubMed] [Google Scholar]
  33. Suzuki H., Parente A., Farina B., Greco L., La Montagna R., Leone E. Complete amino-acid sequence of bovine seminal ribonuclease, a dimeric protein from seminal plasma. Biol Chem Hoppe Seyler. 1987 Oct;368(10):1305–1312. doi: 10.1515/bchm3.1987.368.2.1305. [DOI] [PubMed] [Google Scholar]
  34. Till M. A., Ghetie V., Gregory T., Patzer E. J., Porter J. P., Uhr J. W., Capon D. J., Vitetta E. S. HIV-infected cells are killed by rCD4-ricin A chain. Science. 1988 Nov 25;242(4882):1166–1168. doi: 10.1126/science.2847316. [DOI] [PubMed] [Google Scholar]
  35. Tomlinson J. A., Walker V. M., Flewett T. H., Barclay G. R. The inhibition of infection by cucumber mosaic virus and influenza virus by extracts from Phytolacca americana. J Gen Virol. 1974 Feb;22(2):225–232. doi: 10.1099/0022-1317-22-2-225. [DOI] [PubMed] [Google Scholar]
  36. Tsubota H., Winkler G., Meade H. M., Jakubowski A., Thomas D. W., Letvin N. L. CD4-Pseudomonas exotoxin conjugates delay but do not fully inhibit human immunodeficiency virus replication in lymphocytes in vitro. J Clin Invest. 1990 Nov;86(5):1684–1689. doi: 10.1172/JCI114892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vescia S., Tramontano D., Augusti-Tocco G., D'Alessio G. In vitro studies on selective inhibition of tumor cell growth by seminal ribonuclease. Cancer Res. 1980 Oct;40(10):3740–3744. [PubMed] [Google Scholar]
  38. Wachinger M., Samtleben R., Gerhäuser C., Wagner H., Erfle V. Bryodin, a single-chain ribosome-inactivating protein, selectively inhibits the growth of HIV-1-infected cells and reduces HIV-1 production. Res Exp Med (Berl) 1993;193(1):1–12. doi: 10.1007/BF02576205. [DOI] [PubMed] [Google Scholar]
  39. Wu Y., Mikulski S. M., Ardelt W., Rybak S. M., Youle R. J. A cytotoxic ribonuclease. Study of the mechanism of onconase cytotoxicity. J Biol Chem. 1993 May 15;268(14):10686–10693. [PubMed] [Google Scholar]
  40. Wyatt S. D., Shepherd R. J. Isolation and characterization of a virus inhibitor from Phytolacca americana. Phytopathology. 1969 Dec;59(12):1787–1794. [PubMed] [Google Scholar]
  41. Yamaizumi M., Uchida T., Okada Y. Macromolecules can penetrate the host cell membrane during the early period of incubation with HVJ (Sendai virus). Virology. 1979 May;95(1):218–221. doi: 10.1016/0042-6822(79)90418-5. [DOI] [PubMed] [Google Scholar]
  42. Youle R. J., Newton D., Wu Y. N., Gadina M., Rybak S. M. Cytotoxic ribonucleases and chimeras in cancer therapy. Crit Rev Ther Drug Carrier Syst. 1993;10(1):1–28. [PubMed] [Google Scholar]
  43. Zarling J. M., Moran P. A., Haffar O., Sias J., Richman D. D., Spina C. A., Myers D. E., Kuebelbeck V., Ledbetter J. A., Uckun F. M. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies. Nature. 1990 Sep 6;347(6288):92–95. doi: 10.1038/347092a0. [DOI] [PubMed] [Google Scholar]
  44. Zhou A., Hassel B. A., Silverman R. H. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell. 1993 Mar 12;72(5):753–765. doi: 10.1016/0092-8674(93)90403-d. [DOI] [PubMed] [Google Scholar]

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