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Evidence for antiviral effect of nitric oxide. Inhibition of herpes simplex virus type 1 replication.

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  • 1. Department of Internal Medicine, University of Cincinnati College of Medicine, OH 45267-0560.
      Authors
    • Croen KD 1
    (1 author)

The Journal of Clinical Investigation, 01 Jun 1993, 91(6):2446-2452
https://doi.org/10.1172/jci116479 PMID: 8390481 PMCID: PMC443304

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Abstract 

Nitric oxide (NO) has antimicrobial activity against a wide spectrum of infectious pathogens, but an antiviral effect has not been reported. The impact of NO, from endogenous and exogenous sources, on herpes simplex virus type 1 (HSV 1) replication was studied in vitro. HSV 1 replication in RAW 264.7 macrophages was reduced 1,806-fold in monolayers induced to make NO by activation with gamma IFN and LPS. A competitive and a noncompetitive inhibitor of nitric oxide synthetase substantially reduced the antiviral effect of activated RAW macrophages. S-nitroso-L-acetyl penicillamine (SNAP) is a donor of NO and was added to the media of infected monolayers to assess the antiviral properties of NO in the absence of gamma IFN and LPS. A single dose of S-nitroso-L-acetyl penicillamine 3 h after infection inhibited HSV 1 replication in Vero, HEp2, and RAW 264.7 cells in a dose-dependent manner. Neither virucidal nor cytocidal effects of NO were observed under conditions that inhibited HSV 1 replication. Nitric oxide had inhibitory effects, comparable to that of gamma IFN/LPS, on protein and DNA synthesis as well as on cell replication. This report demonstrates that, among its diverse properties, NO has an antiviral effect.

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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1993 Jun; 91(6): 2446–2452.
PMCID: PMC443304
PMID: 8390481

Evidence for antiviral effect of nitric oxide. Inhibition of herpes simplex virus type 1 replication.

K D Croen
Author information Copyright and License information Disclaimer

Abstract

Nitric oxide (NO) has antimicrobial activity against a wide spectrum of infectious pathogens, but an antiviral effect has not been reported. The impact of NO, from endogenous and exogenous sources, on herpes simplex virus type 1 (HSV 1) replication was studied in vitro. HSV 1 replication in RAW 264.7 macrophages was reduced 1,806-fold in monolayers induced to make NO by activation with gamma IFN and LPS. A competitive and a noncompetitive inhibitor of nitric oxide synthetase substantially reduced the antiviral effect of activated RAW macrophages. S-nitroso-L-acetyl penicillamine (SNAP) is a donor of NO and was added to the media of infected monolayers to assess the antiviral properties of NO in the absence of gamma IFN and LPS. A single dose of S-nitroso-L-acetyl penicillamine 3 h after infection inhibited HSV 1 replication in Vero, HEp2, and RAW 264.7 cells in a dose-dependent manner. Neither virucidal nor cytocidal effects of NO were observed under conditions that inhibited HSV 1 replication. Nitric oxide had inhibitory effects, comparable to that of gamma IFN/LPS, on protein and DNA synthesis as well as on cell replication. This report demonstrates that, among its diverse properties, NO has an antiviral effect.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Corey L, Spear PG. Infections with herpes simplex viruses (2). N Engl J Med. 1986 Mar 20;314(12):749–757. [Abstract] [Google Scholar]
  • Stevens JG. Human herpesviruses: a consideration of the latent state. Microbiol Rev. 1989 Sep;53(3):318–332. [Europe PMC free article] [Abstract] [Google Scholar]
  • Thompson RL, Devi-Rao GV, Stevens JG, Wagner EK. Rescue of a herpes simplex virus type 1 neurovirulence function with a cloned DNA fragment. J Virol. 1985 Aug;55(2):504–508. [Europe PMC free article] [Abstract] [Google Scholar]
  • Chou J, Kern ER, Whitley RJ, Roizman B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science. 1990 Nov 30;250(4985):1262–1266. [Abstract] [Google Scholar]
  • Kohl S. Role of antibody-dependent cellular cytotoxicity in defense against herpes simplex virus infections. Rev Infect Dis. 1991 Jan-Feb;13(1):108–114. [Abstract] [Google Scholar]
  • Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992 Feb 1;116(3):197–202. [Abstract] [Google Scholar]
  • Kohl S, Loo LS, Drath DB, Cox P. Interleukin-2 protects neonatal mice from lethal herpes simplex virus infection: a macrophage-mediated, gamma interferon-induced mechanism. J Infect Dis. 1989 Feb;159(2):239–247. [Abstract] [Google Scholar]
  • Hayward A, Laszlo M, Vafai A. Human newborn natural killer cell responses to activation by monoclonal antibodies. Effect of culture with herpes simplex virus. J Immunol. 1989 Feb 15;142(4):1139–1143. [Abstract] [Google Scholar]
  • Oh SH, Gonik B, Greenberg SB, Kohl S. Enhancement of human neonatal natural killer cytotoxicity to herpes simplex virus with use of recombinant human interferons: lack of neonatal response to gamma interferon. J Infect Dis. 1986 Apr;153(4):791–793. [Abstract] [Google Scholar]
  • Kohl S. Protection against murine neonatal herpes simplex virus infection by lymphokine-treated human leukocytes. J Immunol. 1990 Jan 1;144(1):307–312. [Abstract] [Google Scholar]
  • Feduchi E, Alonso MA, Carrasco L. Human gamma interferon and tumor necrosis factor exert a synergistic blockade on the replication of herpes simplex virus. J Virol. 1989 Mar;63(3):1354–1359. [Europe PMC free article] [Abstract] [Google Scholar]
  • Wong GH, Goeddel DV. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. Nature. 323(6091):819–822. [Abstract] [Google Scholar]
  • Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [Abstract] [Google Scholar]
  • Bredt DS, Snyder SH. Nitric oxide, a novel neuronal messenger. Neuron. 1992 Jan;8(1):3–11. [Abstract] [Google Scholar]
  • Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 1991 Feb;14(2):60–67. [Abstract] [Google Scholar]
  • Nathan CF, Hibbs JB., Jr Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991 Feb;3(1):65–70. [Abstract] [Google Scholar]
  • Granger DL, Hibbs JB, Jr, Perfect JR, Durack DT. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J Clin Invest. 1988 Apr;81(4):1129–1136. [Europe PMC free article] [Abstract] [Google Scholar]
  • James SL, Glaven J. Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J Immunol. 1989 Dec 15;143(12):4208–4212. [Abstract] [Google Scholar]
  • Liew FY, Millott S, Parkinson C, Palmer RM, Moncada S. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol. 1990 Jun 15;144(12):4794–4797. [Abstract] [Google Scholar]
  • Denis M. Interferon-gamma-treated murine macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates. Cell Immunol. 1991 Jan;132(1):150–157. [Abstract] [Google Scholar]
  • Alspaugh JA, Granger DL. Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis. Infect Immun. 1991 Jul;59(7):2291–2296. [Europe PMC free article] [Abstract] [Google Scholar]
  • Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther. 1981 Sep;218(3):739–749. [Abstract] [Google Scholar]
  • Stuehr DJ, Fasehun OA, Kwon NS, Gross SS, Gonzalez JA, Levi R, Nathan CF. Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB J. 1991 Jan;5(1):98–103. [Abstract] [Google Scholar]
  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. [Abstract] [Google Scholar]
  • Becker Y, Olshevsky U, Levitt J. The role of arginine in the replication of herpes simplex virus. J Gen Virol. 1967 Oct;1(4):471–478. [Abstract] [Google Scholar]
  • Samuel CE. Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology. 1991 Jul;183(1):1–11. [Abstract] [Google Scholar]
  • Beutler B, Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. [Abstract] [Google Scholar]
  • Bohn H, Beyerle R, Martorana PA, Schönafinger K. CAS 936, a novel syndnonimine with direct vasodilating and nitric oxide-donating properties: effects on isolated blood vessels. J Cardiovasc Pharmacol. 1991 Oct;18(4):522–527. [Abstract] [Google Scholar]
  • Hibbs JB, Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. [Abstract] [Google Scholar]
  • Albina JE, Abate JA, Henry WL., Jr Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. J Immunol. 1991 Jul 1;147(1):144–148. [Abstract] [Google Scholar]
  • Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651–4655. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kilbourn RG, Griffith OW. Overproduction of nitric oxide in cytokine-mediated and septic shock. J Natl Cancer Inst. 1992 Jun 3;84(11):827–831. [Abstract] [Google Scholar]
  • Cai W, Schaffer PA. A cellular function can enhance gene expression and plating efficiency of a mutant defective in the gene for ICP0, a transactivating protein of herpes simplex virus type 1. J Virol. 1991 Aug;65(8):4078–4090. [Europe PMC free article] [Abstract] [Google Scholar]
  • Goldstein DJ, Weller SK. Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant. Virology. 1988 Sep;166(1):41–51. [Abstract] [Google Scholar]
  • Daikoku T, Yamamoto N, Maeno K, Nishiyama Y. Role of viral ribonucleotide reductase in the increase of dTTP pool size in herpes simplex virus-infected Vero cells. J Gen Virol. 1991 Jun;72(Pt 6):1441–1444. [Abstract] [Google Scholar]
  • Lepoivre M, Fieschi F, Coves J, Thelander L, Fontecave M. Inactivation of ribonucleotide reductase by nitric oxide. Biochem Biophys Res Commun. 1991 Aug 30;179(1):442–448. [Abstract] [Google Scholar]
  • Jacobson JG, Leib DA, Goldstein DJ, Bogard CL, Schaffer PA, Weller SK, Coen DM. A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells. Virology. 1989 Nov;173(1):276–283. [Abstract] [Google Scholar]
  • Katz JP, Bodin ET, Coen DM. Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants. J Virol. 1990 Sep;64(9):4288–4295. [Europe PMC free article] [Abstract] [Google Scholar]
  • Bredt DS, Snyder SH. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9030–9033. [Europe PMC free article] [Abstract] [Google Scholar]
  • Ignarro LJ. Signal transduction mechanisms involving nitric oxide. Biochem Pharmacol. 1991 Feb 15;41(4):485–490. [Abstract] [Google Scholar]
  • Sainz de la Maza M, Wells PA, Foster CS. Cyclic nucleotide modulation of herpes simplex virus latency and reactivation. Invest Ophthalmol Vis Sci. 1989 Oct;30(10):2154–2159. [Abstract] [Google Scholar]
  • Leib DA, Nadeau KC, Rundle SA, Schaffer PA. The promoter of the latency-associated transcripts of herpes simplex virus type 1 contains a functional cAMP-response element: role of the latency-associated transcripts and cAMP in reactivation of viral latency. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):48–52. [Europe PMC free article] [Abstract] [Google Scholar]
  • Sawtell NM, Thompson RL. Herpes simplex virus type 1 latency-associated transcription unit promotes anatomical site-dependent establishment and reactivation from latency. J Virol. 1992 Apr;66(4):2157–2169. [Europe PMC free article] [Abstract] [Google Scholar]
  • Tenser RB, Hay KA, Edris WA. Latency-associated transcript but not reactivatable virus is present in sensory ganglion neurons after inoculation of thymidine kinase-negative mutants of herpes simplex virus type 1. J Virol. 1989 Jun;63(6):2861–2865. [Europe PMC free article] [Abstract] [Google Scholar]
  • Leib DA, Bogard CL, Kosz-Vnenchak M, Hicks KA, Coen DM, Knipe DM, Schaffer PA. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol. 1989 Jul;63(7):2893–2900. [Europe PMC free article] [Abstract] [Google Scholar]
  • Aimi Y, Fujimura M, Vincent SR, Kimura H. Localization of NADPH-diaphorase-containing neurons in sensory ganglia of the rat. J Comp Neurol. 1991 Apr 15;306(3):382–392. [Abstract] [Google Scholar]
  • Verge VM, Xu Z, Xu XJ, Wiesenfeld-Hallin Z, Hökfelt T. Marked increase in nitric oxide synthase mRNA in rat dorsal root ganglia after peripheral axotomy: in situ hybridization and functional studies. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11617–11621. [Europe PMC free article] [Abstract] [Google Scholar]
  • Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6711–6715. [Europe PMC free article] [Abstract] [Google Scholar]
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