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摘要: 单纯疱疹病毒1型（herpes simplex virus type 1，HSV-1）是一种能够在各类人群中携带和传播并能引起包括口唇疱疹、荚膜炎、角膜炎和病毒性脑炎等疾病的重要病原体。虽然已有多种类型的HSV-1疫苗处于研发的不同阶段，但仍没有商业化的疫苗上市销售。临床上使用的特异性抗HSV-1药物如阿昔洛韦、伐昔洛韦和喷昔洛韦等也面临严重的抗药性威胁，开发新的特异性抗HSV-1药物是当前所面临的主要任务之一。siRNA是一种长度为20～25 核苷酸的双链RNA，通过在转录后水平上沉默基因表达发挥干扰作用。siRNA作为一种新的、有潜力的抗病毒药物备受关注，发展也较为迅速。综述近年来siRNA在抗HSV-1方面的研究进展，包括靶向HSV-1关键基因和HSV-1互作的宿主细胞基因的siRNA设计、递送和靶向策略。Abstract: HSV-1 is an important pathogen that can be carried and transmitted in various populations and can cause diseases including herpes labialis, capsulatus, keratitis and viral encephalitis. Although there are several types of HSV-1 vaccines in various stages of development, there is still no commercially available vaccine on the market. The specific anti-HSV-1 drugs used in clinical practice, such as acyclovir, valaciclovir and peniclovir, are also facing the serious threat of resistance. The development of new specific anti-HSV-1 drugs is one of the main tasks currently faced. siRNA is a double-stranded RNA with a length of 20-25 nucleotides that plays an interfering role by silencing gene expression at the post-transcriptional level. As a new and potential antiviral drug, siRNA has attracted much attention and developed rapidly. In this paper, we review the recent progress of siRNA in anti-HSV-1 research, including the design, delivery and targeting strategies of siRNA targeting key HSV-1 genes and HSV-1 interacting host cell genes.
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Key words:
- siRNA /
- HSV-1 /
- Research Progress
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表 1 靶向HSV-1编码基因的siRNA
Table 1. Summary of siRNAs targeting HSV-1-encoded genes
靶基因 siRNA 正向 （5′-3′） 反向 （5′-3′） 干扰效率（%） 参考文献 UL18 siUL18-1 GCACCGUUAACCUUCGCAATT UUGCGAAGGUUAACGGUGCTT 86.78 [25] siUL18-2 GUCCUUAACAUGGUUUACUTT AGUAAACCAUGUUAAGGACTT 60.00 siUL18-3 CCAUCAUCCUUACGCUAAUTT AUUAGCGUAAGGAUGAUGGTT 87.25 siUL18-4 CCCGUUAUACGCUAUCCCUAA AGGGAUAGCGUAUAACGGGGG 65.00 UL19 siUL19-1 CCAGCGACGUACAGUUUAATT UUAAACUGUACGUCGCUGGCG 79.71 siUL19-2 CUUUUGUGCCGAUGCATT UGCAUCGGCAACAACAAAGTT 81.52 siUL19-3 CGACCGACGUCAACUACUUTT AAGUAGUUGACGUCGGUCGTT 81.52 siUL19-4 CCAGCGACGUACAGUUUAATT UUAAACUGUACGUCGCUGGTT 78.86 UL26 siUL26-1 CCGUUAACAACAUGAUGCUTT AGCAUCAUGUUGGUUAACGGCG 40.00 siUL26-2 CCGAUUUGUUCGUCUCUCATT UGAGAGACGAACAAAUCGGCG 81.21 siUL26-3 CUGUUGUACCUGAUCACCAAC UGGUGAUCAGGUACAACAGGC NC siUL26-4 CCGUUAACAACAUGAUGCUGC AGCAUCAUGUUGGUUAACGGCG 10.00 UL26.5 siUL26.5 CCGAUUUGUUCGUCUCUCAUU UUGGCUAAACAAGCAGAGAGU 52.12 UL28 shRNAUL28 GATCCGCAGGTGCAGACCTATG
TGTTTTCAAGAGAACACATAGG
TCTGCACCTGCTTTTTTGGAAANC DAY1 50.00 [29] DAY2 70.00 DAY3 60.00 DAY4 40.00 UL29 shRNAUL29 GATCCGCAATCAATTCCAACCG
GTGCTTCAAGAGAGCACCGGTT
GGAATTGATTGCTTTTTTGGAAANC DAY1 60.00 DAY2 80.00 DAY3 60.00 DAY4 50.00 UL30 siRNA-4 GGUACAACAUCAUCAACUUTT AAGUUGAUGAUGUUGUACCTT 6 h 60.00 [40] 12 h 80.00 UL35 siUL35-1 CACGCAAACAACACGUUUATT UAACGUGUUGUUGCGUGGG 50.00 [25] siUL35-2 GCCACCAAUAACUCUCAGUTT ACUGAGAGUUAUUGGUGGCCA 55.95 siUL35-3 CUCUCAGUUUAUCAUGGAUTT AUCCAUGAUAAACUGAGAGTT 22.00 siUL35-4 GUUUGUCGUCGAGAACCUTT AGGUUCUCGAACGACAAACGG 30.00 UL38 siUL38-1 GGCCUAGUGUCGUUUAACUTT AGUUAAACGACACUAGGCCCG NC [25] siUL38-2 GGAUCACCAAACCGAUUCATT UGAAUCGUGUUGGUGAUCCCGG 10.00 siUL38-3 GCGUUUCUGUACCUGGUAUTT AUACCAGGUACAGAAACGCCG 82.48 siUL38-4 GUUGUGUGUACGUGAUCAATT UUGAUCACGUACACACAACAC NC UL39
siRNA1 CUGCACCAUGAUCAUCGACdTdT GUCGAUGAUCAUGGUGCAGdTdT 29.63 [33] siRNA2 AUCGGCCCUGAAGUAUGAGdTdT CUCAUACUUCAGGGCCGAUUG 27.07 siRNA3 GCGCUGCGACAAUAUCUUCdTdT GAAGAUAUUGUCGCAGCGCUG NC siRNA4 CCAUAGCCAAUCCAUGACCdTdT GGUCAUGGAUUGGCUAUGGUC NC UL40 siRNA-1 GACGACCUGGUUACGGAAAdTdT UUUCCGUAACCAGGUCGUCGG 2.73 [30] siRNA-2 AAUGCAUCGAAGUCGUACAdTdT UGUACGACUUCGAUGCAUUCC 69.83 siRNA-3 UCACCUGCCAGUCAAACGAdTdT UCGUUUGACUGGCAGGUGACC 67.94 siRNA-4 AAAUUGGUGUGUUUGUCGGUG AAAUUGGUGUGUUUGUCGGUG 81.31 ICP4 siRNA GCAACAGCAGCUCCUUCAUdTdT dTdTCGUUGUCGUCGAGGAAGUA 12 h 69.00 24 h 95.00 VP16 siRNA-1 GGUACUUUAUGGUGUUGAUTT AUCAACACCAUAAAGUACCTT NC [31，40] 
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表 2 靶向宿主基因与HSV-1相互作用的siRNA
Table 2. Summary of siRNA targeting host genes interacting with HSV-1
靶基因 siRNA 正向（5′-3′） 参考文献 INSM1 siINSM1 UCCGCAAGCUGCACUUCGATT [45] SNF2H siRNA5 GGAAUGGUAUACUCGGAUA [48] siRNA6 GGGCAAA UAGAUUCGAGUA siRNA7 GGAUUUACCAAUUGGAAUA siRNA8 GUUCUUUCCUCCACGUUUA REST siREST GUGAUACUGUAGAUUACAC [49] coREST sicoREST AAGAUUGUCCCGUUCUUGACU [59] TSG101 siTSG101 CCUCCAGUCUUCUCUCGUCTT [52] ALIX siALIX GCCGCUGGUGAAGUUCAUCTT
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[1] Looker K J,Magaret A S,May M T,et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012[J]. PLoS One,2015,10(10):e0140765. doi: 10.1371/journal.pone.0140765 [2] James C,Harfouche M,Welton N J,et al. Herpes simplex virus: Global infection prevalence and incidence estimates,2016[J]. Bull World Health Organ,2020,98(5):315-329. doi: 10.2471/BLT.19.237149 [3] Looker K J,Magaret A S,May M T,et al. First estimates of the global and regional incidence of neonatal herpes infection[J]. Lancet Glob Health,2017,5(3):e300-e309. doi: 10.1016/S2214-109X(16)30362-X [4] Xu F,Sternberg M R,Kottiri B J,et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States[J]. Jama,2006,296(8):964-973. doi: 10.1001/jama.296.8.964 [5] Navarro-Bielsa A,Gracia-Cazana T,Aldea-Manrique B,et al. COVID-19 infection and vaccines: Potential triggers of Herpesviridae reactivation[J]. An Bras Dermatol,2023,98(3):347-354. doi: 10.1016/j.abd.2022.09.004 [6] Whitley RJRoizman B. Herpes simplex virus infections[J]. The Lancet,2001,357(9267):1513-1518. doi: 10.1016/S0140-6736(00)04638-9 [7] Marcocci M E,Napoletani G,Protto V,et al. Herpes simplex virus-1 in the brain: The dark side of a sneaky infection[J]. Trends Microbiol,2020,28(10):808-820. doi: 10.1016/j.tim.2020.03.003 [8] De Chiara G,Marcocci M E,Sgarbanti R,et al. Infectious agents and neurodegeneration[J]. Mol Neurobiol,2012,46(3):614-638. doi: 10.1007/s12035-012-8320-7 [9] De Clercq E. A 40-year journey in search of selective antiviral chemotherapy[J]. Annual Review of Pharmacology and Toxicology,2011,51(1):1-24. doi: 10.1146/annurev-pharmtox-010510-100228 [10] De Clercq E. Antivirals: Past,present and future[J]. Biochem Pharmacol,2013,85(6):727-744. doi: 10.1016/j.bcp.2012.12.011 [11] Burrel S,Boutolleau D,Azar G,et al. Phenotypic and genotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrent herpetic keratitis[J]. J Clin Virol,2013,58(1):321-324. doi: 10.1016/j.jcv.2013.05.001 [12] Sadowski L A,Upadhyay R,Greeley Z W,et al. Current drugs to treat infections with herpes simplex viruses-1 and -2[J]. Viruses,2021,13(7):1228. doi: 10.3390/v13071228 [13] Preda M,Manolescu L S C,Chivu R D. Advances in alpha herpes viruses vaccines for human[J]. Vaccines (Basel),2023,11(6):1094. doi: 10.3390/vaccines11061094 [14] Pushparaj P N,Aarthi J J,Manikandan J,et al. siRNA,miRNA,and shRNA: In vivo applications[J]. J Dent Res,2008,87(11):992-1003. doi: 10.1177/154405910808701109 [15] Hu B,Zhong L,Weng Y,et al. Therapeutic siRNA: State of the art[J]. Signal Transduct Target Ther,2020,5(1):101. doi: 10.1038/s41392-020-0207-x [16] Tan F L,Yin J Q. RNAi,a new therapeutic strategy against viral infection[J]. Cell Res,2004,14(6):460-466. doi: 10.1038/sj.cr.7290248 [17] Guo S,Kemphues K J. par-1,a gene required for establishing polarity in C. elegans embryos,encodes a putative Ser/Thr kinase that is asymmetrically distributed[J]. Cell,1995,81(4):611-620. doi: 10.1016/0092-8674(95)90082-9 [18] Fire A,Xu S,Montgomery M K,et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J]. Nature,1998,391(6669):806-811. doi: 10.1038/35888 [19] Elbashir S M,Lendeckel W,Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs[J]. Genes Dev,2001,15(2):188-200. doi: 10.1101/gad.862301 [20] Elbashir S M,Harborth J,Lendeckel W,et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J]. Nature,2001,411(6836):494-498. doi: 10.1038/35078107 [21] Hammond S M,Bernstein E,Beach D,et al. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells[J]. Nature,2000,404(6775):293-296. doi: 10.1038/35005107 [22] Saurabh S,Vidyarthi A S,Prasad D. RNA interference: concept to reality in crop improvement[J]. Planta,2014,239(3):543-564. doi: 10.1007/s00425-013-2019-5 [23] Carthew R W,Sontheimer E J. Origins and mechanisms of miRNAs and siRNAs[J]. Cell,2009,136(4):642-655. doi: 10.1016/j.cell.2009.01.035 [24] Griffiths S J,Haas J. siRNA screening for genes involved in HSV-1 replication[J]. Bio Protoc,2014,4(16):e1209. [25] Jin F,Li S,Zheng K,et al. Silencing herpes simplex virus type 1 capsid protein encoding genes by siRNA: A promising antiviral therapeutic approach[J]. PLoS One,2014,9(5):e96623. doi: 10.1371/journal.pone.0096623 [26] Jbara-Agbaria D,Blondzik S,Burger-Kentischer A,et al. Liposomal siRNA formulations for the treatment of herpes simplex virus-1: In vitro characterization of physicochemical properties and activity,and in vivo biodistribution and toxicity studies[J]. Pharmaceutics,2022,14(3):633. doi: 10.3390/pharmaceutics14030633 [27] Taylor T J,Knipe D M. Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication,repair,recombination,and chromatin remodeling proteins with ICP8[J]. J Virol,2004,78(11):5856-5866. doi: 10.1128/JVI.78.11.5856-5866.2004 [28] Bryant K F,Yan Z,Dreyfus D H,et al. Identification of a divalent metal cation binding site in herpes simplex virus 1 (HSV-1) ICP8 required for HSV replication[J]. J Virol,2012,86(12):6825-6834. doi: 10.1128/JVI.00374-12 [29] Song B,Liu X,Wang Q,et al. Adenovirus-mediated shRNA interference against HSV-1 replication in vitro[J]. J Neurovirol,2016,22(6):799-807. doi: 10.1007/s13365-016-0453-4 [30] Silva A P,Lopes J F,Paula V S. RNA interference inhibits herpes simplex virus type 1 isolated from saliva samples and mucocutaneous lesions[J]. Braz J Infect Dis,2014,18(4):441-444. doi: 10.1016/j.bjid.2014.01.011 [31] Duan F,Ni S,Nie Y,et al. Small interfering RNA targeting for infected-cell polypeptide 4 inhibits herpes simplex virus type 1 replication in retinal pigment epithelial cells[J]. Clinical & Experimental Ophthalmology,2012,40(2):195-204. [32] Liu Y T,Song B,Wang Y L,et al. [SiRNA targeting ICP4 attenuates HSV-1 replication][J]. Bing Du Xue Bao,2010,26(3):163-169. [33] Zhe R,Mei-Ying Z,Kitazato K,et al. Effect of siRNA on HSV-1 plaque formation and relative expression levels of UL39 mRNA[J]. Arch Virol,2008,153(7):1401-1406. doi: 10.1007/s00705-008-0110-1 [34] Ren Z,Li S,Wang Q L,et al. Effect of siRNAs on HSV-1 plaque formation and relative expression levels of RR mRNA[J]. Virol Sin,2011,26(1):40-46. doi: 10.1007/s12250-011-3162-9 [35] Heming J D,Conway J F,Homa F L. Herpesvirus capsid assembly and DNA packaging[J]. Adv Anat Embryol Cell Biol,2017,223:119-142. [36] Paavilainen H,Lehtinen J,Romanovskaya A,et al. Inhibition of clinical pathogenic herpes simplex virus 1 strains with enzymatically created siRNA pools[J]. J Med Virol,2016,88(12):2196-2205. doi: 10.1002/jmv.24578 [37] Paavilainen H,Lehtinen J,Romanovskaya A,et al. Topical treatment of herpes simplex virus infection with enzymatically created siRNA swarm[J]. Antivir Ther,2017,22(7):631-637. doi: 10.3851/IMP3153 [38] Kalke K,Lehtinen J,Gnjatovic J,et al. Herpes simplex virus type 1 clinical isolates respond to UL29-targeted siRNA swarm treatment independent of their acyclovir sensitivity[J]. Viruses,2020,12(12):1434. doi: 10.3390/v12121434 [39] Levanova A A,Kalke K M,Lund L M,et al. Enzymatically synthesized 2'-fluoro-modified Dicer-substrate siRNA swarms against herpes simplex virus demonstrate enhanced antiviral efficacy and low cytotoxicity[J]. Antiviral Res,2020,182:104916. doi: 10.1016/j.antiviral.2020.104916 [40] Zhang Y Q,Lai W,Li H,et al. Inhibition of herpes simplex virus type 1 by small interfering RNA[J]. Clin Exp Dermatol,2008,33(1):56-61. [41] Zhu Q C,Ren Z,Zhang C L,et al. Silencing HSV1 gD expression in cultured cells by RNA interference[J]. Bing Du Xue Bao,2007,23(1):22-27. [42] Bhuyan P K,Kariko K,Capodici J,et al. Short interfering RNA-mediated inhibition of herpes simplex virus type 1 gene expression and function during infection of human keratinocytes[J]. J Virol,2004,78(19):10276-10281. doi: 10.1128/JVI.78.19.10276-10281.2004 [43] 吴长静,邹雨芳,黄新伟. HSV1感染中的表观遗传调控机制研究进展[J]. 昆明医科大学学报,2024,45(1):172-178. doi: 10.12259/j.issn.2095-610X.S20240129 [44] Liang Y,Vogel J L,Narayanan A,et al. Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency[J]. Nat Med,2009,15(11):1312-1317. doi: 10.1038/nm.2051 [45] Kamakura M,Goshima F,Luo C,et al. Herpes simplex virus induces the marked up-regulation of the zinc finger transcriptional factor INSM1,which modulates the expression and localization of the immediate early protein ICP0[J]. Virol J,2011,8:257. doi: 10.1186/1743-422X-8-257 [46] Olivo J F,Guille F,Lobel B. Microscopic hematuria. Semiologic value in urology. Management of microscopic hematuria[J]. J Urol (Paris),1989,95(8):453-458. [47] Sanders I,Boyer MF,Fraser N W. Early nucleosome deposition on,and replication of,HSV DNA requires cell factor PCNA[J]. J Neurovirol,2015,21(4):358-369. doi: 10.1007/s13365-015-0321-7 [48] Bryant K F,Colgrove R C,Knipe D M. Cellular SNF2H chromatin-remodeling factor promotes herpes simplex virus 1 immediate-early gene expression and replication[J]. MBio,2011,2(1):e00330-10. [49] Zhou G,Te D,Roizman B. The CoREST/REST repressor is both necessary and inimical for expression of herpes simplex virus genes[J]. mBio,2010,2(1):e00313-10. [50] Mccullough J,Colf LA,Sundquist W I. Membrane fission reactions of the mammalian ESCRT pathway[J]. Annu Rev Biochem,2013,82:663-692. doi: 10.1146/annurev-biochem-072909-101058 [51] Pawliczek T,Crump C M. Herpes simplex virus type 1 production requires a functional ESCRT-III complex but is independent of TSG101 and ALIX expression[J]. J Virol,2009,83(21):11254-11264. doi: 10.1128/JVI.00574-09 [52] Barnes J,Wilson D W. The ESCRT-II subunit EAP20/VPS25 and the bro1 domain proteins HD-PTP and BROX are individually dispensable for herpes simplex virus 1 replication[J]. J Virol,2020,94(4):e01641-19. [53] Russell T,Samolej J,Hollinshead M,et al. Novel role for ESCRT-III component CHMP4C in the integrity of the endocytic network utilized for herpes simplex virus envelopment[J]. mBio,2021,12(3):e02183-20. [54] Huber M T,Wisner T W,Hegde N R,et al. Herpes simplex virus with highly reduced gD levels can efficiently enter and spread between human keratinocytes[J]. J Virol,2001,75(21):10309-10318. doi: 10.1128/JVI.75.21.10309-10318.2001 [55] Petermann P,Thier K,Rahn E,et al. Entry mechanisms of herpes simplex virus 1 into murine epidermis: Involvement of nectin-1 and herpesvirus entry mediator as cellular receptors[J]. J Virol,2015,89(1):262-274. doi: 10.1128/JVI.02917-14 [56] Sayers C L,Elliott G. Herpes simplex virus 1 enters human keratinocytes by a nectin-1-dependent,rapid plasma membrane fusion pathway that functions at low temperature[J]. J Virol,2016,90(22):10379-10389. doi: 10.1128/JVI.01582-16 [57] Tiwari V,Oh M J,Kovacs M,et al. Role for nectin-1 in herpes simplex virus 1 entry and spread in human retinal pigment epithelial cells[J]. FEBS J,2008,275(21):5272-5285. doi: 10.1111/j.1742-4658.2008.06655.x [58] Cheshenko N,Trepanier J B,Segarra T J,et al. HSV usurps eukaryotic initiation factor 3 subunit M for viral protein translation: novel prevention target[J]. PLoS One,2010,5(7):e11829. doi: 10.1371/journal.pone.0011829 [59] Gu H,Liang Y,Mandel G,et al. Components of the REST/CoREST/histone deacetylase repressor complex are disrupted,modified,and translocated in HSV-1-infected cells[J]. Proc Natl Acad Sci U S A,2005,102(21):7571-7576. doi: 10.1073/pnas.0502658102 -
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