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. 1997 Feb;71(2):1718–1725. doi: 10.1128/jvi.71.2.1718-1725.1997

Induction of CD4 expression and human immunodeficiency virus type 1 replication by mutants of the interferon-inducible protein kinase PKR.

K Nagai 1, A H Wong 1, S Li 1, W N Tam 1, A R Cuddihy 1, N Sonenberg 1, M B Mathews 1, J Hiscott 1, M A Wainberg 1, A E Koromilas 1
PMCID: PMC191238  PMID: 8995707

Abstract

Replication of the human immunodeficiency virus type 1 (HIV-1) is inhibited by interferons (IFNs), and the IFN-inducible protein kinase PKR is thought to mediate this effect by regulating protein synthesis. Here we report that ectopic expression of dominant negative PKR mutants in Jurkat cells induces HIV-1 replication. Specifically, expression of CD4 is upregulated by the PKR mutants, and this correlates with an induction of HIV-1 binding and proviral DNA synthesis upon HIV-1 infection. Moreover, activation of NF-kappaB was induced by an RNA binding-defective mutant of PKR. Thus, it appears that PKR, in addition to translational control, is involved in HIV-1 replication by modulating virus binding through the regulation of CD4 expression and virus gene expression through the activation of NF-kappaB.

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Selected References

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  1. Baca-Regen L., Heinzinger N., Stevenson M., Gendelman H. E. Alpha interferon-induced antiretroviral activities: restriction of viral nucleic acid synthesis and progeny virion production in human immunodeficiency virus type 1-infected monocytes. J Virol. 1994 Nov;68(11):7559–7565. doi: 10.1128/jvi.68.11.7559-7565.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barber G. N., Jagus R., Meurs E. F., Hovanessian A. G., Katze M. G. Molecular mechanisms responsible for malignant transformation by regulatory and catalytic domain variants of the interferon-induced enzyme RNA-dependent protein kinase. J Biol Chem. 1995 Jul 21;270(29):17423–17428. doi: 10.1074/jbc.270.29.17423. [DOI] [PubMed] [Google Scholar]
  3. Barber G. N., Wambach M., Thompson S., Jagus R., Katze M. G. Mutants of the RNA-dependent protein kinase (PKR) lacking double-stranded RNA binding domain I can act as transdominant inhibitors and induce malignant transformation. Mol Cell Biol. 1995 Jun;15(6):3138–3146. doi: 10.1128/mcb.15.6.3138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bates P. Chemokine receptors and HIV-1: an attractive pair? Cell. 1996 Jul 12;86(1):1–3. doi: 10.1016/s0092-8674(00)80070-7. [DOI] [PubMed] [Google Scholar]
  5. Beauparlant P., Kwon H., Clarke M., Lin R., Sonenberg N., Wainberg M., Hiscott J. Transdominant mutants of I kappa B alpha block Tat-tumor necrosis factor synergistic activation of human immunodeficiency virus type 1 gene expression and virus multiplication. J Virol. 1996 Sep;70(9):5777–5785. doi: 10.1128/jvi.70.9.5777-5785.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bour S., Geleziunas R., Wainberg M. A. The human immunodeficiency virus type 1 (HIV-1) CD4 receptor and its central role in promotion of HIV-1 infection. Microbiol Rev. 1995 Mar;59(1):63–93. doi: 10.1128/mr.59.1.63-93.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chong K. L., Feng L., Schappert K., Meurs E., Donahue T. F., Friesen J. D., Hovanessian A. G., Williams B. R. Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2. EMBO J. 1992 Apr;11(4):1553–1562. doi: 10.1002/j.1460-2075.1992.tb05200.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coccia E. M., Krust B., Hovanessian A. G. Specific inhibition of viral protein synthesis in HIV-infected cells in response to interferon treatment. J Biol Chem. 1994 Sep 16;269(37):23087–23094. [PubMed] [Google Scholar]
  9. Cosentino G. P., Venkatesan S., Serluca F. C., Green S. R., Mathews M. B., Sonenberg N. Double-stranded-RNA-dependent protein kinase and TAR RNA-binding protein form homo- and heterodimers in vivo. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9445–9449. doi: 10.1073/pnas.92.21.9445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  11. DeLuca C., Roulston A., Koromilas A., Wainberg M. A., Hiscott J. Chronic human immunodeficiency virus type 1 infection of myeloid cells disrupts the autoregulatory control of the NF-kappaB/Rel pathway via enhanced IkappaBalpha degradation. J Virol. 1996 Aug;70(8):5183–5193. doi: 10.1128/jvi.70.8.5183-5193.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Donzé O., Jagus R., Koromilas A. E., Hershey J. W., Sonenberg N. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J. 1995 Aug 1;14(15):3828–3834. doi: 10.1002/j.1460-2075.1995.tb00052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Edery I., Petryshyn R., Sonenberg N. Activation of double-stranded RNA-dependent kinase (dsl) by the TAR region of HIV-1 mRNA: a novel translational control mechanism. Cell. 1989 Jan 27;56(2):303–312. doi: 10.1016/0092-8674(89)90904-5. [DOI] [PubMed] [Google Scholar]
  14. Fernie B. F., Poli G., Fauci A. S. Alpha interferon suppresses virion but not soluble human immunodeficiency virus antigen production in chronically infected T-lymphocytic cells. J Virol. 1991 Jul;65(7):3968–3971. doi: 10.1128/jvi.65.7.3968-3971.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fisher A. G., Collalti E., Ratner L., Gallo R. C., Wong-Staal F. A molecular clone of HTLV-III with biological activity. Nature. 1985 Jul 18;316(6025):262–265. doi: 10.1038/316262a0. [DOI] [PubMed] [Google Scholar]
  16. Gatignol A., Buckler-White A., Berkhout B., Jeang K. T. Characterization of a human TAR RNA-binding protein that activates the HIV-1 LTR. Science. 1991 Mar 29;251(5001):1597–1600. doi: 10.1126/science.2011739. [DOI] [PubMed] [Google Scholar]
  17. Green S. R., Mathews M. B. Two RNA-binding motifs in the double-stranded RNA-activated protein kinase, DAI. Genes Dev. 1992 Dec;6(12B):2478–2490. doi: 10.1101/gad.6.12b.2478. [DOI] [PubMed] [Google Scholar]
  18. Gunnery S., Green S. R., Mathews M. B. Tat-responsive region RNA of human immunodeficiency virus type 1 stimulates protein synthesis in vivo and in vitro: relationship between structure and function. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11557–11561. doi: 10.1073/pnas.89.23.11557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gunnery S., Rice A. P., Robertson H. D., Mathews M. B. Tat-responsive region RNA of human immunodeficiency virus 1 can prevent activation of the double-stranded-RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8687–8691. doi: 10.1073/pnas.87.22.8687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hansen B. D., Nara P. L., Maheshwari R. K., Sidhu G. S., Bernbaum J. G., Hoekzema D., Meltzer M. S., Gendelman H. E. Loss of infectivity by progeny virus from alpha interferon-treated human immunodeficiency virus type 1-infected T cells is associated with defective assembly of envelope gp120. J Virol. 1992 Dec;66(12):7543–7548. doi: 10.1128/jvi.66.12.7543-7548.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hershey J. W. Protein phosphorylation controls translation rates. J Biol Chem. 1989 Dec 15;264(35):20823–20826. [PubMed] [Google Scholar]
  22. Judware R., Petryshyn R. Mechanism of action of a cellular inhibitor of the dsRNA-dependent protein kinase from 3T3-F442A cells. J Biol Chem. 1992 Oct 25;267(30):21685–21690. [PubMed] [Google Scholar]
  23. Katze M. G. Regulation of the interferon-induced PKR: can viruses cope? Trends Microbiol. 1995 Feb;3(2):75–78. doi: 10.1016/s0966-842x(00)88880-0. [DOI] [PubMed] [Google Scholar]
  24. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  25. Koromilas A. E., Cantin C., Craig A. W., Jagus R., Hiscott J., Sonenberg N. The interferon-inducible protein kinase PKR modulates the transcriptional activation of immunoglobulin kappa gene. J Biol Chem. 1995 Oct 27;270(43):25426–25434. doi: 10.1074/jbc.270.43.25426. [DOI] [PubMed] [Google Scholar]
  26. Koromilas A. E., Roy S., Barber G. N., Katze M. G., Sonenberg N. Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science. 1992 Sep 18;257(5077):1685–1689. doi: 10.1126/science.1382315. [DOI] [PubMed] [Google Scholar]
  27. Kumar A., Haque J., Lacoste J., Hiscott J., Williams B. R. Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6288–6292. doi: 10.1073/pnas.91.14.6288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lee M. H., Sano K., Morales F. E., Imagawa D. T. Comparable sensitivities for detection of human immunodeficiency virus by sensitive reverse transcriptase and antigen capture enzyme-linked immunosorbent assays. J Clin Microbiol. 1988 Feb;26(2):371–374. doi: 10.1128/jcm.26.2.371-374.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lee T. G., Tang N., Thompson S., Miller J., Katze M. G. The 58,000-dalton cellular inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR) is a member of the tetratricopeptide repeat family of proteins. Mol Cell Biol. 1994 Apr;14(4):2331–2342. doi: 10.1128/mcb.14.4.2331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Maitra R. K., McMillan N. A., Desai S., McSwiggen J., Hovanessian A. G., Sen G., Williams B. R., Silverman R. H. HIV-1 TAR RNA has an intrinsic ability to activate interferon-inducible enzymes. Virology. 1994 Nov 1;204(2):823–827. doi: 10.1006/viro.1994.1601. [DOI] [PubMed] [Google Scholar]
  31. Maran A., Maitra R. K., Kumar A., Dong B., Xiao W., Li G., Williams B. R., Torrence P. F., Silverman R. H. Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. Science. 1994 Aug 5;265(5173):789–792. doi: 10.1126/science.7914032. [DOI] [PubMed] [Google Scholar]
  32. McMillan N. A., Chun R. F., Siderovski D. P., Galabru J., Toone W. M., Samuel C. E., Mak T. W., Hovanessian A. G., Jeang K. T., Williams B. R. HIV-1 Tat directly interacts with the interferon-induced, double-stranded RNA-dependent kinase, PKR. Virology. 1995 Nov 10;213(2):413–424. doi: 10.1006/viro.1995.0014. [DOI] [PubMed] [Google Scholar]
  33. Meurs E. F., Galabru J., Barber G. N., Katze M. G., Hovanessian A. G. Tumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):232–236. doi: 10.1073/pnas.90.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Meurs E. F., McMillan N., Williams B. R., Hovanessian A. G., Southern P. J. Human PKR transfected into murine cells stimulates expression of genes under control of the HIV1 or HTLV-I LTR. Virology. 1995 Dec 20;214(2):653–659. doi: 10.1006/viro.1995.0080. [DOI] [PubMed] [Google Scholar]
  35. Meurs E. F., Watanabe Y., Kadereit S., Barber G. N., Katze M. G., Chong K., Williams B. R., Hovanessian A. G. Constitutive expression of human double-stranded RNA-activated p68 kinase in murine cells mediates phosphorylation of eukaryotic initiation factor 2 and partial resistance to encephalomyocarditis virus growth. J Virol. 1992 Oct;66(10):5805–5814. doi: 10.1128/jvi.66.10.5805-5814.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Meurs E., Chong K., Galabru J., Thomas N. S., Kerr I. M., Williams B. R., Hovanessian A. G. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990 Jul 27;62(2):379–390. doi: 10.1016/0092-8674(90)90374-n. [DOI] [PubMed] [Google Scholar]
  37. Meylan P. R., Guatelli J. C., Munis J. R., Richman D. D., Kornbluth R. S. Mechanisms for the inhibition of HIV replication by interferons-alpha, -beta, and -gamma in primary human macrophages. Virology. 1993 Mar;193(1):138–148. doi: 10.1006/viro.1993.1110. [DOI] [PubMed] [Google Scholar]
  38. Mundschau L. J., Faller D. V. Oncogenic ras induces an inhibitor of double-stranded RNA-dependent eukaryotic initiation factor 2 alpha-kinase activation. J Biol Chem. 1992 Nov 15;267(32):23092–23098. [PubMed] [Google Scholar]
  39. Offermann M. K., Zimring J., Mellits K. H., Hagan M. K., Shaw R., Medford R. M., Mathews M. B., Goodbourn S., Jagus R. Activation of the double-stranded-RNA-activated protein kinase and induction of vascular cell adhesion molecule-1 by poly (I).poly (C) in endothelial cells. Eur J Biochem. 1995 Aug 15;232(1):28–36. doi: 10.1111/j.1432-1033.1995.tb20777.x. [DOI] [PubMed] [Google Scholar]
  40. Park H., Davies M. V., Langland J. O., Chang H. W., Nam Y. S., Tartaglia J., Paoletti E., Jacobs B. L., Kaufman R. J., Venkatesan S. TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4713–4717. doi: 10.1073/pnas.91.11.4713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Perno C. F., Bergamini A., Pesce C. D., Milanese G., Capozzi M., Aquaro S., Thaisrivongs S., Tarpley W. G., Zon G., D'Agostini C. Inhibition of the protease of human immunodeficiency virus blocks replication and infectivity of the virus in chronically infected macrophages. J Infect Dis. 1993 Nov;168(5):1148–1156. doi: 10.1093/infdis/168.5.1148. [DOI] [PubMed] [Google Scholar]
  42. Pitha P. M. Multiple effects of interferon on the replication of human immunodeficiency virus type 1. Antiviral Res. 1994 Jul;24(2-3):205–219. doi: 10.1016/0166-3542(94)90068-x. [DOI] [PubMed] [Google Scholar]
  43. Poli G., Orenstein J. M., Kinter A., Folks T. M., Fauci A. S. Interferon-alpha but not AZT suppresses HIV expression in chronically infected cell lines. Science. 1989 May 5;244(4904):575–577. doi: 10.1126/science.2470148. [DOI] [PubMed] [Google Scholar]
  44. Proud C. G. PKR: a new name and new roles. Trends Biochem Sci. 1995 Jun;20(6):241–246. doi: 10.1016/s0968-0004(00)89025-8. [DOI] [PubMed] [Google Scholar]
  45. Roulston A., Lin R., Beauparlant P., Wainberg M. A., Hiscott J. Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors. Microbiol Rev. 1995 Sep;59(3):481–505. doi: 10.1128/mr.59.3.481-505.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Roy S., Agy M., Hovanessian A. G., Sonenberg N., Katze M. G. The integrity of the stem structure of human immunodeficiency virus type 1 Tat-responsive sequence of RNA is required for interaction with the interferon-induced 68,000-Mr protein kinase. J Virol. 1991 Feb;65(2):632–640. doi: 10.1128/jvi.65.2.632-640.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Roy S., Katze M. G., Parkin N. T., Edery I., Hovanessian A. G., Sonenberg N. Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1 tat gene product. Science. 1990 Mar 9;247(4947):1216–1219. doi: 10.1126/science.2180064. [DOI] [PubMed] [Google Scholar]
  48. Schindler C., Darnell J. E., Jr Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem. 1995;64:621–651. doi: 10.1146/annurev.bi.64.070195.003201. [DOI] [PubMed] [Google Scholar]
  49. Shirazi Y., Pitha P. M. Alpha interferon inhibits early stages of the human immunodeficiency virus type 1 replication cycle. J Virol. 1992 Mar;66(3):1321–1328. doi: 10.1128/jvi.66.3.1321-1328.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shirazi Y., Pitha P. M. Interferon alpha-mediated inhibition of human immunodeficiency virus type 1 provirus synthesis in T-cells. Virology. 1993 Mar;193(1):303–312. doi: 10.1006/viro.1993.1126. [DOI] [PubMed] [Google Scholar]
  51. Smith M. S., Thresher R. J., Pagano J. S. Inhibition of human immunodeficiency virus type 1 morphogenesis in T cells by alpha interferon. Antimicrob Agents Chemother. 1991 Jan;35(1):62–67. doi: 10.1128/aac.35.1.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Zack J. A., Arrigo S. J., Weitsman S. R., Go A. S., Haislip A., Chen I. S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. doi: 10.1016/0092-8674(90)90802-l. [DOI] [PubMed] [Google Scholar]

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