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. 1994 Nov;68(11):7559–7565. doi: 10.1128/jvi.68.11.7559-7565.1994

Alpha interferon-induced antiretroviral activities: restriction of viral nucleic acid synthesis and progeny virion production in human immunodeficiency virus type 1-infected monocytes.

L Baca-Regen 1, N Heinzinger 1, M Stevenson 1, H E Gendelman 1
PMCID: PMC237202  PMID: 7933143

Abstract

Alpha interferon (IFN-alpha) restricts multiple steps of the human immunodeficiency virus type 1 (HIV-1) life cycle. A well-described effect of IFN-alpha is in the modulation of viral nucleic acid synthesis. We demonstrate that IFN-alpha influences HIV-1 DNA synthesis principally by reducing the production of late products of reverse transcription. The magnitude of IFN-alpha-induced downregulation of HIV-1 DNA and/or progeny virion production was dependent on the IFN-alpha concentration, the duration of cytokine administration, the multiplicity of infection, the viral strain, and the cycles of viral infection. Interestingly, reductions in viral DNAs could not fully account for the observed IFN-alpha-induced abrogation of progeny virion production. These data, by our investigation of both single-cycle and spreading viral infections, support a predominant but not exclusive effect of IFN-alpha on viral DNA synthesis.

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Selected References

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  1. Baca L. M., Genis P., Kalvakolanu D., Sen G., Meltzer M. S., Zhou A., Silverman R., Gendelman H. E. Regulation of interferon-alpha-inducible cellular genes in human immunodeficiency virus-infected monocytes. J Leukoc Biol. 1994 Mar;55(3):299–309. doi: 10.1002/jlb.55.3.299. [DOI] [PubMed] [Google Scholar]
  2. Brown P. O., Bowerman B., Varmus H. E., Bishop J. M. Correct integration of retroviral DNA in vitro. Cell. 1987 May 8;49(3):347–356. doi: 10.1016/0092-8674(87)90287-x. [DOI] [PubMed] [Google Scholar]
  3. Bukrinsky M. I., Haggerty S., Dempsey M. P., Sharova N., Adzhubel A., Spitz L., Lewis P., Goldfarb D., Emerman M., Stevenson M. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature. 1993 Oct 14;365(6447):666–669. doi: 10.1038/365666a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bukrinsky M. I., Sharova N., Dempsey M. P., Stanwick T. L., Bukrinskaya A. G., Haggerty S., Stevenson M. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6580–6584. doi: 10.1073/pnas.89.14.6580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bukrinsky M. I., Sharova N., McDonald T. L., Pushkarskaya T., Tarpley W. G., Stevenson M. Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6125–6129. doi: 10.1073/pnas.90.13.6125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
  7. Finter N. B., Chapman S., Dowd P., Johnston J. M., Manna V., Sarantis N., Sheron N., Scott G., Phua S., Tatum P. B. The use of interferon-alpha in virus infections. Drugs. 1991 Nov;42(5):749–765. doi: 10.2165/00003495-199142050-00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Folks T. M., Powell D., Lightfoote M., Koenig S., Fauci A. S., Benn S., Rabson A., Daugherty D., Gendelman H. E., Hoggan M. D. Biological and biochemical characterization of a cloned Leu-3- cell surviving infection with the acquired immune deficiency syndrome retrovirus. J Exp Med. 1986 Jul 1;164(1):280–290. doi: 10.1084/jem.164.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Francis M. L., Meltzer M. S., Gendelman H. E. Interferons in the persistence, pathogenesis, and treatment of HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):199–207. doi: 10.1089/aid.1992.8.199. [DOI] [PubMed] [Google Scholar]
  10. Friedman R. L., Manly S. P., McMahon M., Kerr I. M., Stark G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell. 1984 Oct;38(3):745–755. doi: 10.1016/0092-8674(84)90270-8. [DOI] [PubMed] [Google Scholar]
  11. Gendelman H. E., Baca L. M., Kubrak C. A., Genis P., Burrous S., Friedman R. M., Jacobs D., Meltzer M. S. Induction of IFN-alpha in peripheral blood mononuclear cells by HIV-infected monocytes. Restricted antiviral activity of the HIV-induced IFN. J Immunol. 1992 Jan 15;148(2):422–429. [PubMed] [Google Scholar]
  12. Gendelman H. E., Baca L. M., Turpin J., Kalter D. C., Hansen B., Orenstein J. M., Dieffenbach C. W., Friedman R. M., Meltzer M. S. Regulation of HIV replication in infected monocytes by IFN-alpha. Mechanisms for viral restriction. J Immunol. 1990 Oct 15;145(8):2669–2676. [PubMed] [Google Scholar]
  13. Gendelman H. E., Narayan O., Molineaux S., Clements J. E., Ghotbi Z. Slow, persistent replication of lentiviruses: role of tissue macrophages and macrophage precursors in bone marrow. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7086–7090. doi: 10.1073/pnas.82.20.7086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gendelman H. E., Orenstein J. M., Martin M. A., Ferrua C., Mitra R., Phipps T., Wahl L. A., Lane H. C., Fauci A. S., Burke D. S. Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med. 1988 Apr 1;167(4):1428–1441. doi: 10.1084/jem.167.4.1428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gessani S., Puddu P., Varano B., Borghi P., Conti L., Fantuzzi L., Belardelli F. Induction of beta interferon by human immunodeficiency virus type 1 and its gp120 protein in human monocytes-macrophages: role of beta interferon in restriction of virus replication. J Virol. 1994 Mar;68(3):1983–1986. doi: 10.1128/jvi.68.3.1983-1986.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Huang Z. B., Potash M. J., Simm M., Shahabuddin M., Chao W., Gendelman H. E., Eden E., Volsky D. J. Infection of macrophages with lymphotropic human immunodeficiency virus type 1 can be arrested after viral DNA synthesis. J Virol. 1993 Nov;67(11):6893–6896. doi: 10.1128/jvi.67.11.6893-6896.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kalter D. C., Nakamura M., Turpin J. A., Baca L. M., Hoover D. L., Dieffenbach C., Ralph P., Gendelman H. E., Meltzer M. S. Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes. J Immunol. 1991 Jan 1;146(1):298–306. [PubMed] [Google Scholar]
  19. Lane H. C., Davey V., Kovacs J. A., Feinberg J., Metcalf J. A., Herpin B., Walker R., Deyton L., Davey R. T., Jr, Falloon J. Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med. 1990 Jun 1;112(11):805–811. doi: 10.7326/0003-4819-112-11-805. [DOI] [PubMed] [Google Scholar]
  20. Lane H. C., Kovacs J. A., Feinberg J., Herpin B., Davey V., Walker R., Deyton L., Metcalf J. A., Baseler M., Salzman N. Anti-retroviral effects of interferon-alpha in AIDS-associated Kaposi's sarcoma. Lancet. 1988 Nov 26;2(8622):1218–1222. doi: 10.1016/s0140-6736(88)90811-2. [DOI] [PubMed] [Google Scholar]
  21. Layne S. P., Dembo M. The auto-regulation model: a unified concept of how HIV regulates its infectivity, pathogenesis and persistence. Int Rev Immunol. 1992;8(1):1–32. doi: 10.3109/08830189209056638. [DOI] [PubMed] [Google Scholar]
  22. Lori F., di Marzo Veronese F., de Vico A. L., Lusso P., Reitz M. S., Jr, Gallo R. C. Viral DNA carried by human immunodeficiency virus type 1 virions. J Virol. 1992 Aug;66(8):5067–5074. doi: 10.1128/jvi.66.8.5067-5074.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Meylan P. R., Spina C. A., Richman D. D., Kornbluth R. S. In vitro differentiation of monocytoid THP-1 cells affects their permissiveness for HIV strains: a model system for studying the cellular basis of HIV differential tropism. Virology. 1993 Mar;193(1):256–267. doi: 10.1006/viro.1993.1121. [DOI] [PubMed] [Google Scholar]
  25. O'Brien W. A., Namazi A., Kalhor H., Mao S. H., Zack J. A., Chen I. S. Kinetics of human immunodeficiency virus type 1 reverse transcription in blood mononuclear phagocytes are slowed by limitations of nucleotide precursors. J Virol. 1994 Feb;68(2):1258–1263. doi: 10.1128/jvi.68.2.1258-1263.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pitha P. M. Multiple effects of interferon on HIV-1 replication. J Interferon Res. 1991 Dec;11(6):313–318. doi: 10.1089/jir.1991.11.313. [DOI] [PubMed] [Google Scholar]
  27. Samuel C. E. Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology. 1991 Jul;183(1):1–11. doi: 10.1016/0042-6822(91)90112-o. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. Trono D. Partial reverse transcripts in virions from human immunodeficiency and murine leukemia viruses. J Virol. 1992 Aug;66(8):4893–4900. doi: 10.1128/jvi.66.8.4893-4900.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wells D. E., Chatterjee S., Mulligan M. J., Compans R. W. Inhibition of human immunodeficiency virus type 1-induced cell fusion by recombinant human interferons. J Virol. 1991 Nov;65(11):6325–6330. doi: 10.1128/jvi.65.11.6325-6330.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zack J. A., Arrigo S. J., Chen I. S. Control of expression and cell tropism of human immunodeficiency virus type 1. Adv Virus Res. 1990;38:125–146. doi: 10.1016/s0065-3527(08)60861-1. [DOI] [PubMed] [Google Scholar]
  33. de Wit R., Schattenkerk J. K., Boucher C. A., Bakker P. J., Veenhof K. H., Danner S. A. Clinical and virological effects of high-dose recombinant interferon-alpha in disseminated AIDS-related Kaposi's sarcoma. Lancet. 1988 Nov 26;2(8622):1214–1217. doi: 10.1016/s0140-6736(88)90810-0. [DOI] [PubMed] [Google Scholar]

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