siRNA intervention inhibiting viral replication and delivery strategies for treating herpes simplex viral infection

  • Vyshnavi Manda
  • Venkata Rao Josyula
  • Raghu Chandrashekar HariharapuraEmail author


The effective treatment of herpes simplex virus (HSV) infections generally involves the use of antiviral nucleoside drugs, but with increasing reports of antiviral resistance, the use of these drugs is challenged. Hence, a need arises to explore alternate treatment options. In this review we have discussed various targets that have been explored to control the HSV replication using siRNA therapeutics. We have also discussed the advantages of targeting a less explored UL10 gene to develop an alternate therapeutic intervention. Gene silencing can induce an inhibitory activity to virus spread and infection. The capacity and suitability of UL10 gene as siRNA induced silencing target in eliciting the desired antiviral effect in patients is identified and particularly discussed. The major challenge associated with the siRNA therapeutics is their delivery. The various viable delivery options, that are being explored in the recent times is summarized and different delivery pathways and strategies are reviewed as a part of the study.


Herpes simplex virus Gene silencing siRNA siRNA delivery UL10 gene 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Blondeau C, Pelchen-Matthews A, Mlcochova P, Marsh M, Milne R, Towers G. Tetherin restricts herpes simplex virus 1 and Is antagonized by glycoprotein M. J Virol. 2013;87(24):13124–33.Google Scholar
  2. 2.
    Chouljenko D, Kim I, Chouljenko V, Subramanian R, Walker J, Kousoulas K. Functional hierarchy of herpes simplex virus 1 viral glycoproteins in cytoplasmic virion envelopment and egress. J Virol. 2012;86(8):4262–70.Google Scholar
  3. 3.
    Crump CM, Bruun B, Bell S, Pomeranz LE, Minson T, Browne HM. Alpha herpesvirus glycoprotein M causes the relocalization of plasma membrane proteins. J Gen Virol. 2004;85:3517–27.Google Scholar
  4. 4.
    da Silva A, Lopes JF, Paula VS. RNA interference inhibits herpes simplex virus type 1 isolated from saliva samples and mucocutaneous lesions. Braz J Infect Dis. 2014;18(4):441–4.Google Scholar
  5. 5.
    da Silva A, Raposo JV, Pereira TC, Pinto MA, de Paula VS. Effects of RNA interference therapy against herpes simplex virus type 1 encephalitis. Antivir Ther. 2016;20(3):225–35.Google Scholar
  6. 6.
    Duan F, Ni S, Nie Y, Huang Q, Wu K. Small interfering RNA targeting for infected-cell polypeptide 4 inhibits herpes simplex virus type 1 replication in retinal pigment epithelial cells. Clin Exp Ophthalmol. 2012;40(2):195–204.Google Scholar
  7. 7.
    El Kasmi I, Lippé R. Herpes simplex virus 1 gN partners with gM To modulate the viral fusion machinery. J Virol. 2015;89(4):2313–23.Google Scholar
  8. 8.
    Gavrilov K, Saltzman W. Therapeutic siRNA: principles, challenges, and strategies. Yale J Biol Med. 2012;85:187–200.Google Scholar
  9. 9.
    Gilleron J, Paramasivam P, Zeigerer A, Querbes W, Marsico G, Andree C, Seifert S, Amaya P, Stöter M, Koteliansky V, Waldmann H, Fitzgerald K, Kalaidzidis Y, Akinc A, Maier M, Manoharan M, Bickle M, Zerial M. Identification of siRNA delivery enhancers by a chemical library screen. Nucleic Acids Res. 2015;43(16):7984–8001.Google Scholar
  10. 10.
    Hochberg CH, Schneider JA, Dandona R, Lakshmi V, Kumar GA, Sudha T, Akbar M, Ahmed GMM, Ramgopal SP, Armbruster B, Alary M, Dandona L. Population and dyadic-based seroincidence of herpes simplex virus-2 and syphilis in southern India. Sex Transm Infect. 2015;91(5):375–82.Google Scholar
  11. 11.
    Jiang Y, Huo S, Hardie J, Liang X, Rotello V. Progress and perspective of inorganic nanoparticle-based siRNA delivery systems. Expert Opin Drug Deliv. 2016;13(4):547–59.Google Scholar
  12. 12.
    Jin F, Li S, Zheng K, Zhuo C, Ma K, Chen M, Wang Q, Zhang P, Fan J, Ren Z, Wang Y. Silencing herpes simplex virus type 1 capsid protein encoding genes by siRNA: a promising antiviral therapeutic approach. PLOS ONE. 2014;9(5):96623.Google Scholar
  13. 13.
    Kim I, Chouljenko V, Walker J, Kousoulas K. Herpes simplex virus 1 glycoprotein M and the membrane-associated protein UL11 are required for virus-induced cell fusion and efficient virus entry. J Virol. 2013;87(14):8029–37.Google Scholar
  14. 14.
    Kodama Y, Shiokawa Y, Nakamura T, Kurosaki T, Aki K, Nakagawa H, Muro T, Kitahara T, Higuchi N, Sasaki H. Novel siRNA delivery system using a ternary polymer complex with strong silencing effect and no cytotoxicity. Biol Pharm Bull. 2014;37(8):1274–81.Google Scholar
  15. 15.
    Kozielski K, Tzeng S, Green J. Bioengineered nanoparticles for siRNA delivery. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnol. 2013;5(5):449–68.Google Scholar
  16. 16.
    Lau S, Crump C. HSV-1 gM and the gK/pUL20 complex are important for the localization of gD and gH/L to viral assembly sites. Viruses. 2015;7(3):915–38.Google Scholar
  17. 17.
    Leege T, Fuchs W, Granzow H, Kopp M, Klupp B, Mettenleiter T. Effects of simultaneous deletion of pUL11 and glycoprotein M on virion maturation of herpes simplex virus type 1. J Virol. 2008;83(2):896–907.Google Scholar
  18. 18.
    MacLean C, Robertson L, Jamieson F. Characterization of the UL10 gene product of herpes simplex virus type 1 and investigation of its role in vivo. J Gen Virol. 1993;74(6):975–83.Google Scholar
  19. 19.
    Paavilainen H, Lehtinen J, Romanovskaya A, Nygårdas M, Bamford DH, Poranen MM, Hukkanen V. Inhibition of clinical pathogenic herpes simplex virus 1 strains with enzymatically created siRNA pools. J Med Virol. 2016;88(12):2196–205.Google Scholar
  20. 20.
    Paavilainen H, Lehtinen J, Romanovskaya A, Nygårdas M, Bamford DH, Poranen MM, Hukkanen V. Topical treatment of herpes simplex virus infection with enzymatically created siRNA swarm. Antivir Ther. 2017;22(7):631–7.Google Scholar
  21. 21.
    Patwardhan V, Bhalla P. Role of type-specific herpes simplex virus-1 and 2 serology as a diagnostic modality in patients with clinically suspected genital herpes: a comparative study in Indian population from a tertiary care hospital. Indian J Pathol Microbiol. 2016;59(3):318–21.Google Scholar
  22. 22.
    Ren Y, Bell S, Zenner H, Lau S, Crump C. Glycoprotein M is important for the efficient incorporation of glycoprotein H–L into herpes simplex virus type 1 particles. J Gen Virol. 2011;93(2):319–29.Google Scholar
  23. 23.
    Salzano G, Costa D, Torchilin V. siRNA delivery by stimuli-sensitive nanocarriers. Curr Pharm Des. 2015;21(31):4566–73.Google Scholar
  24. 24.
    Saran N, Bupesh G, Magesh S, Vennila S, Anandharaj B, Anupama CP, Kaveri K, Gunasekaran P. Epidemiological studies and molecular characterization of herpes simplex virus among Urban population in Chennai, Tamilnadu. Epidemiol: Open Access. 2015;5(02):187.Google Scholar
  25. 25.
    Sarett S, Nelson C, Duvall C. Technologies for controlled, local delivery of siRNA. J Control Release. 2015;218:94–113.Google Scholar
  26. 26.
    Shim M, Kwon Y. Efficient and targeted delivery of siRNA in vivo. FEBS J. 2010;277(23):4814–27.Google Scholar
  27. 27.
    Song B, Liu X, Wang Q, Zhang R, Yang T, Han Z, Xu Y. Adenovirus-mediated shRNA interference against HSV-1 replication in vitro. J Neurovirol. 2016;22(6):799–807.Google Scholar
  28. 28.
    Striebinger H, Funk C, Raschbichler V, Bailer S. Subcellular trafficking and functional relationship of the HSV-1 glycoproteins N and M. Viruses. 2016;8(3):83.Google Scholar
  29. 29.
    Tatiparti K, Sau S, Kashaw S, Iyer A. siRNA delivery strategies: a comprehensive review of recent developments. Nanomaterials. 2017;7(4):77.Google Scholar
  30. 30.
    Wang J, Lu Z, Wientjes M, Au J. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 2010;12(4):492–503.Google Scholar
  31. 31.
    Wang Z, Fan P, Zhao Y, Zhang S, Lu J, Xie W, Jiang Y, Lei F, Xu N. NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription. Cell Mol Life Sci. 2017;74(6):1117–31.Google Scholar
  32. 32.
    Whitley R, Kimberlin D, Roizman B. Herpes simplex viruses. Clin Infect Dis. 1998;26(3):541–53.Google Scholar
  33. 33.
    Wu Y, Navarro F, Lal A, Basar E, Pandey RK, Manoharan M, Feng Y, Lee SJ, Lieberman J, Palliser D. Durable protection from Herpes Simplex Virus-2 transmission following intravaginal application of siRNAs targeting both a viral and host gene. Cell Host Microbe. 2009;5:84–94.Google Scholar
  34. 34.
    Xu C, Wang J. Delivery systems for siRNA drug development in cancer therapy. Asian J Pharm Sci. 2015;10(1):1–12.Google Scholar
  35. 35.
    Zhang Y, Lai W, Li H, Li G. Inhibition of herpes simplex virus type 1 by small interfering RNA. Clin Exp Dermatol. 2008;33(1):56–61.Google Scholar
  36. 36.
    Zhang J, Nagel C, Sodeik B, Lippe R. Early, active, and specific localization of herpes simplex virus type 1 gM to nuclear membranes. J Virol. 2009;83(24):12984–97.Google Scholar

Copyright information

© Indian Virological Society 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical SciencesManipal Academy of Higher Education (MAHE)ManipalIndia
  2. 2.Manipal McGill Centre for Infectious Diseases, Prasanna School of Public HealthManipal Academy of Higher Education (MAHE)ManipalIndia

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