Herpetic encephalitis (HSE) is caused mainly by herpes simplex virus type 1 (HSV-1) with an annual incidence of 1–4 cases/million inhabitants. Currently, HSE treatment faces difficulties such as the use of antivirals with elevated toxicity, metabolic side effects and HSV-1 resistance. An alternative to antivirals is the use of small interfering RNA (siRNA) as a viral replication inhibitor. In this work, siRNA targeting the UL-39 region was evaluated for HSE treatment in vivo.
Methods
BALB/c mice were inoculated with HSV-1 and treated with siRNA. The treatment was evaluated through kinetics of HSV-1 replication inhibition, number of siRNA doses administered and treatment with siRNA plus acyclovir. All groups were evaluated for signs of HSE, mortality and HSV-1 replication inhibition.
Results
The treated group of the kinetic experiment demonstrated a reduction of HSE signs and an HSV-1 replication inhibition of 43.6–99.9% in the brain and 53–98% in trigeminal ganglia (TG). Animals treated with one or two doses of siRNA had a prolonged survival time, reduced clinical signs of HSE and HSV-1 replication inhibition of 67.7% in brains and 85.7% in TG of animals treated with two doses of siRNA. Also, animals treated with siRNA plus acyclovir demonstrated reduced signs of HSE and mortality, as well as HSV-1 replication inhibition in the brain (83.2%) and TG (74.5%).
Conclusions
These findings demonstrated that siRNA was capable of reducing HSE clinical signs, prolonging survival time and inhibiting HSV-1 replication in mice. Thus, siRNA can be a potential alternative to the standard HSE treatment especially to reduce clinical signs and extend survival time in vivo.
References
1.
StahlJ.P., MaillesA., DacheuxL., MorandP.Epidemiology of viral encephalitis in 2011.Med Mal Infect2011; 41: 453–464.
2.
FatahzadehM., SchwartzR.A.Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management.J Am Acad Dermatol2007; 57: 737–763.
KimberlinD.W.Management of HSV encephalitis in adults and neonates: diagnosis, prognosis and treatment.Herpes2007; 14: 11–16.
5.
De TiègeX., RozenbergF., HeronB.The spectrum of herpes simplex encephalitis in children.Eur J Paediatr Neurol2008; 12: 72–81.
6.
KneenR., JakkaS., MithyanthaR., RiordanA., SolomonT.The management of infants and children treated with aciclovir for suspected viral encephalitis.Arch Dis Child2010; 95: 100–106.
7.
BaringerJ.R.Herpes simplex infections of the nervous system.Neurol Clin2008; 26: 657–674.
8.
ArduinoP.G., PorterS.R.Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management.Oral Dis2006; 12: 254–270.
ErnstM.E., FraneyR.J.Acyclovir- and ganciclovir-induced neurotoxicity.Ann Pharmacother1998; 32: 111–113.
12.
JohnsonG.L., LimonL., TrikhaG., WallH.Acute renal failure and neurotoxicity following oral acyclovir.Ann Pharmacother1994; 28: 460–463.
13.
WilsonS.S., FakiogluE., HeroldB.C.Novel approaches in fighting herpes simplex virus infections.Expert Rev Anti Infect Ther2009; 7: 559–568.
14.
GilbertC., Bestman-SmithJ., BoivinG.Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms.Drug Resist Updat2002; 5: 88–114.
15.
BaconT.H., LevinM.J., LearyJ.J., SariskyR.T., SuttonD.Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy.Clin Microbiol Rev2003; 16: 114–128.
16.
DambrosiS., MartinM., YimK.Neurovirulence and latency of drug-resistant clinical herpes simplex viruses in animal models.J Med Virol2010; 82: 1000–1006.
BrownT.J., McCraryM., TyringS.K.Antiviral agents: Non-antiretroviral [correction of Nonantiviral] drugs.J Am Acad Dermatol2002; 47: 581–599.
19.
HannonG.J., RossiJ.J.Unlocking the potential of the human genome with RNA interference.Nature2004; 431: 371–378.
20.
MelloC.C., ConteD.Jr.. Revealing the world of RNA interference.Nature2004; 431: 338–342.
21.
AlvarezR., ElbashirS., BorlandT.RNA interference-mediated silencing of the respiratory syncytial virus nucleocapsid defines a potent antiviral strategy.Antimicrob Agents Chemother2009; 53: 3952–3962.
22.
KusovY.Y., GosertR., Gauss-MullerV.Replication and in vivo repair of the hepatitis A virus genome lacking the poly(A) tail.J Gen Virol2005; 86: 1363–1368.
23.
CrowtherC., MowaM.B., ElyA., ArbuthnotP.B.Inhibition of hepatitis B virus replication in vivo using helper-dependent adenovirus vectors to deliver antiviral RNAi expression cassettes.Antivir Ther2014; 19: 363–373.
GuptaP.K., SonwaneA.A., SinghN.K.Intracerebral delivery of small interfering RNAs (siRNAs) using adenoviral vector protects mice against lethal peripheral rabies challenge.Virus Res2012; 163: 11–18.
26.
GeisbertT.W., LeeA.C., RobbinsM.Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study.Lancet2010; 375: 1896–1905.
27.
BaiF., WangT., PalU., BaoF., GouldL.H., FikrigE.Use of RNA interference to prevent lethal murine West Nile virus infection.J Infect Dis2005; 191: 1148–1154.
28.
MurakamiM., OtaT., NukuzumaS., TakegamiT.Inhibitory effect of RNAi on Japanese encephalitis virus replication in vitro and in vivo.Microbiol Immunol2005; 49: 1047–1056.
29.
PerseA.S., FreitasJ.L., de PaulaV.S.RNA interference inhibits herpes simplex virus type 1 isolated from saliva samples and mucocutaneous lesions.Braz J Infect Dis2014; 18: 441–444.
30.
ZheR., Mei-YingZ., KitazatoK.Effect of siRNA on HSV-1 plaque formation and relative expression levels of UL39 mRNA.Arch Virol2008; 153: 1401–1406.
31.
KuoY.C., ChenC.C., TsaiW.J., HoY.H.Regulation of herpes simplex virus type 1 replication in Vero cells by Psychotria serpens: relationship to gene expression, DNA replication, and protein synthesis.Antiviral Res2001; 51: 95–109.
32.
De ClercqE., LuczakM.Intranasal challenge of mice with herpes simplex virus: an experimental model for evaluation of the efficacy of antiviral drugs.J Infect Dis1976; 133Suppl 2: A226–A236.
33.
KumarP., WuH., McBrideJ.L.Transvascular delivery of small interfering RNA to the central nervous system.Nature2007; 448: 39–43.
34.
DeLanoR.M., MalleryS.R.Stress-related modulation of central nervous system immunity in a murine model of herpes simplex encephalitis.J Neuroimmunol1998; 89: 51–58.
35.
ShimeldC., EfstathiouS., HillT.Tracking the spread of a lacZ-tagged herpes simplex virus type 1 between the eye and the nervous system of the mouse: comparison of primary and recurrent infection.J Virol2001; 75: 5252–5262.
36.
MossmanK.L., SherburneR., LaveryC., DuncanJ., SmileyJ.R.Evidence that herpes simplex virus VP16 is required for viral egress downstream of the initial envelopment event.J Virol2000; 74: 6287–6299.
37.
LimaG.K., ZoliniG.P., MansurD.S.Toll-like receptor (TLR) 2 and TLR9 expressed in trigeminal ganglia are critical to viral control during herpes simplex virus 1 infection.Am J Pathol2010; 177: 2433–2445.
38.
SellnerJ., DvorakF., ZhouY.Acute and long-term alteration of chemokine mRNA expression after anti-viral and anti-inflammatory treatment in herpes simplex virus encephalitis.Neurosci Lett2005; 374: 197–202.
39.
DavidsonB.L., McCrayP.B.Jr.. Current prospects for RNA interference-based therapies.Nat Rev Genet2011; 12: 329–340.
40.
DykxhoornD.M., LiebermanJ.Knocking down disease with siRNAs.Cell2006; 126: 231–235.
41.
EsiriM.M.Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain.J Neurol Sci1982; 54: 209–226.
42.
KramerA.H.Viral encephalitis in the ICU.Crit Care Clin2013; 29: 621–649.
43.
KennedyP.G., SteinerI.Recent issues in herpes simplex encephalitis.J Neurovirol2013; 19: 346–350.
44.
NicollJ.A., LoveS., KinradeE.Distribution of herpes simplex virus DNA in the brains of human long-term survivors of encephalitis.Neurosci Lett1993; 157: 215–218.
