Animal models of human herpesvirus infection

Abstract

Human herpesvirus, a specific group within the herpesvirus family, is responsible for a variety of human diseases. These viruses can infect humans and other vertebrates, primarily targeting the skin, mucous membranes, and neural tissues, thereby significantly impacting the health of both humans and animals. Animal models are crucial for studying virus pathogenesis, vaccine development, and drug testing. Despite several vaccine candidates being in preclinical and clinical stages, no vaccines are current available to prevent lifelong infections caused by these human herpesviruses, except for varicella-zoster virus (VZV) vaccine. However, the strict host tropism of herpesviruses and other limitations mean that no single animal model can fully replicate all key features of human herpesvirus-associated diseases. This makes it challenging to evaluate vaccines and antivirals against human herpesvirus comprehensively. Herein, we summarize the current animal models used to study the human herpesviruses including α-herpesviruses (herpes simplex virus type 1(HSV-1), HSV-2, VZV), β-herpesviruses (human cytomegalovirus (HCMV), γ-herpesviruses (Epstein–Barr virus (EBV)) and Kaposi's sarcoma herpesvirus (KSHV)). By providing concise information and detailed analysis of the potential, limitations and applications of various models, such as non-human primates, mice, rabbits, guinea pigs, and tree shrews, this summary aims to help researchers efficiently select the most appropriate animal model, offering practical guidance for studying human herpesvirus.

Keywords

animal models / EBV / HSV / human herpesvirus / KSHV / VZV

References

[1] Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. Nat Rev Dis Primers. 2015; 1: 15016.

[2] Cesarman E, Damania B, Krown SE, Martin J, Bower M, Whitby D. Kaposi sarcoma. Nat Rev Dis Primers. 2019; 5(1): 9.

[3] Mocarski ES, Bonyhadi M, Salimi S, McCune JM, Kaneshima H. Human cytomegalovirus in a SCID-hu mouse: thymic epithelial cells are prominent targets of viral replication. Proc Natl Acad Sci USA. 1993; 90(1): 104-108.

[4] Haberthur K, Engelmann F, Park B, et al. CD4 T cell immunity is critical for the control of simian varicella virus infection in a nonhuman primate model of VZV infection. PLoS Pathog. 2011; 7(11): e1002367.

[5] Zhu S, Viejo-Borbolla A. Pathogenesis and virulence of herpes simplex virus. Virulence. 2021; 12(1): 2670-2702.

[6] Li S, Xie Y, Yu C, Zheng C, Xu Z. The battle between host antiviral innate immunity and immune evasion by cytomegalovirus. Cell Mol Life Sci. 2024; 81(1): 341.

[7] Zhu H, Zheng C. The race between host antiviral innate immunity and the immune evasion strategies of herpes simplex virus 1. Microbiol Mol Biol Rev. 2020; 84(4): e0010323.

[8] Lin Y, Zheng C. A tug of war: DNA-sensing antiviral innate immunity and herpes simplex virus type I infection. Front Microbiol. 2019; 10: 2627.

[9] Looker KJ, Magaret AS, Turner KM, Vickerman P, Gottlieb SL, Newman LM. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One. 2015; 10(1): e114989.

[10] Looker KJ, Magaret AS, May MT, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One. 2015; 10(10): e0140765.

[11] Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet. 2001; 357(9267): 1513-1518.

[12] James C, Harfouche M, Welton NJ, et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020; 98(5): 315-329.

[13] Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007; 370(9605): 2127-2137.

[14] Higgins CR, Schofield JK, Tatnall FM, Leigh IM. Natural history, management and complications of herpes labialis. J Med Virol. 1993; Suppl 1: 22-26.

[15] Steiner I, Benninger F. Update on herpes virus infections of the nervous system. Curr Neurol Neurosci Rep. 2013; 13(12): 414.

[16] Aravantinou M, Mizenina O, Calenda G, et al. Experimental oral herpes simplex virus-1 (HSV-1) co-infection in simian immunodeficiency virus (SIV)-infected rhesus macaques. Front Microbiol. 2017; 8: 2342.

[17] Lo M, Zhu J, Hansen SG, et al. Acute infection and subsequent subclinical reactivation of herpes simplex virus 2 after vaginal inoculation of rhesus macaques. J Virol. 2019; 93(2): e01574-18.

[18] Hsu M, Aravantinou M, Menon R, et al. A combination microbicide gel protects macaques against vaginal simian human immunodeficiency virus-reverse transcriptase infection, but only partially reduces herpes simplex virus-2 infection after a single high-dose cochallenge. AIDS Res Hum Retrovir. 2014; 30(2): 174-183.

[19] Wang K, Jordan T, Dowdell K, et al. A nonhuman primate model for genital herpes simplex virus 2 infection that results in vaginal vesicular lesions, virus shedding, and seroconversion. PLoS Pathog. 2024; 20(9): e1012477.

[20] Crostarosa F, Aravantinou M, Akpogheneta OJ, et al. A macaque model to study vaginal HSV-2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy. PLoS One. 2009; 4(11): e8060.

[21] Awasthi S, Hook LM, Shaw CE, et al. An HSV-2 trivalent vaccine is immunogenic in rhesus macaques and highly efficacious in Guinea pigs. PLoS Pathog. 2017; 13(1): e1006141.

[22] Winkler I, Winkelmann E, Scholl T, Rösner M, Jähne G, Helsberg M. Antiviral activity and pharmacokinetics of HOE 602, an acyclic nucleoside, in animal models. Antivir Res. 1990; 14(2): 61-73.

[23] Webre JM, Hill JM, Nolan NM, et al. Rabbit and mouse models of HSV-1 latency, reactivation, and recurrent eye diseases. J Biomed Biotechnol. 2012; 2012: 612316.

[24] Kutle I, Dittrich A, Wirth D. Mouse Models for Human Herpesviruses. Pathogens Basel. 2023; 12(7): 953.

[25] Katsumata K, Chono K, Suzuki H. Antiviral efficacy of the helicase-primase inhibitor amenamevir in murine models of severe herpesvirus infection. Biochem Pharmacol. 2018; 158: 201-206.

[26] Kollias CM, Huneke RB, Wigdahl B, Jennings SR. Animal models of herpes simplex virus immunity and pathogenesis. J Neurovirol. 2015; 21(1): 8-23.

[27] Reinert LS, Rashidi AS, Tran DN, et al. Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. J Clin Invest. 2021; 131(1): e136824.

[28] Cantin E, Tanamachi B, Openshaw H, Mann J, Clarke K. Gamma interferon (IFN-gamma) receptor null-mutant mice are more susceptible to herpes simplex virus type 1 infection than IFN-gamma ligand null-mutant mice. J Virol. 1999; 73(6): 5196-5200.

[29] Lopez C. Genetics of natural resistance to herpesvirus infections in mice. Nature. 1975; 258(Nov 13, 5531): 152-153.

[30] Antony F, Pundkar C, Sandey M, Mishra A, Suryawanshi A. Role of IL-27 in HSV-1-induced herpetic stromal keratitis. J Immunol (Baltimore, Md: 1950). 2023; 211(3): 474-485.

[31] Yang W, Tang CY, Fan DY, et al. Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection. Virol Sin. 2024; 39(2): 251-263.

[32] Kopp SJ, Karaba AH, Cohen LK, Banisadr G, Miller RJ, Muller WJ. Pathogenesis of neonatal herpes simplex 2 disease in a mouse model is dependent on entry receptor expression and route of inoculation. J Virol. 2013; 87(1): 474-481.

[33] Taylor JM, Lin E, Susmarski N, et al. Alternative entry receptors for herpes simplex virus and their roles in disease. Cell Host Microbe. 2007; 2(1): 19-28.

[34] Gonzales GR. Postherpes simplex type 1 neuralgia simulating postherpetic neuralgia. J Pain Symptom Manag. 1992; 7(5): 320-323.

[35] Takasaki I, Andoh T, Shiraki K, Kuraishi Y. Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice. Pain. 2000; 86(1-2): 95-101.

[36] Takasaki I, Sasaki A, Andoh T, Nojima H, Shiraki K, Kuraishi Y. Effects of analgesics on delayed postherpetic pain in mice. Anesthesiology. 2002; 96(5): 1168-1174.

[37] Sasaki A, Serizawa K, Andoh T, Shiraki K, Takahata H, Kuraishi Y. Pharmacological differences between static and dynamic allodynia in mice with herpetic or postherpetic pain. J Pharmacol Sci. 2008; 108(3): 266-273.

[38] Silva JR, Lopes AH, Talbot J, et al. Neuroimmune-glia interactions in the sensory ganglia account for the development of acute herpetic neuralgia. J Neurosci. 2017; 37(27): 6408-6422.

[39] Krohel GB, Richardson JR, Farrell DF. Herpes simplex neuropathy. Neurology. 1976; 26(6 pt. 1): 596-597.

[40] Parr MB, Parr EL. Vaginal immunity in the HSV-2 mouse model. Int Rev Immunol. 2003; 22(1): 43-63.

[41] Krzyzowska M, Orłowski P, Bąska P, Bodera P, Zdanowski R, Stankiewicz W. Role of Fas/FasL signaling in regulation of anti-viral response during HSV-2 vaginal infection in mice. Immunobiology. 2014; 219(12): 932-943.

[42] Baeten JM, Benki S, Chohan V, et al. Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women. AIDS. 2007; 21(13): 1771-1777.

[43] Marshak JO, Dong L, Koelle DM. The murine intravaginal HSV-2 challenge model for investigation of DNA vaccines. Methods Mol Biol (Clifton, NJ). 2020; 2060: 429-454.

[44] Svensson A, Bellner L, Magnusson M, Eriksson K. Role of IFN-alpha/beta signaling in the prevention of genital herpes virus type 2 infection. J Reprod Immunol. 2007; 74(1-2): 114-123.

[45] Beyer CF, Arens MQ, Hill JM, Rose BT, Hill GA, Lin DT. Penetrating keratoplasty in rabbits induces latent HSV-1 reactivation when corticosteroids are used. Curr Eye Res. 1989; 8(12): 1323-1329.

[46] Beyer CF, Tepper DJ, Hill JM. Cryogenic induced ocular HSV-1 reactivation is enhanced by an inhibitor of the lipoxygenase pathway. Curr Eye Res. 1989; 8(12): 1287-1292.

[47] Haruta Y, Rootman DS, Xie LX, Kiritoshi A, Hill JM. Recurrent HSV-1 corneal lesions in rabbits induced by cyclophosphamide and dexamethasone. Invest Ophthalmol Vis Sci. 1989; 30(3): 371-376.

[48] Al-Dujaili LJ, Clerkin PP, Clement C, et al. Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated? Future Microbiol. 2011; 6(8): 877-907.

[49] Margolis TP, Elfman FL, Leib D, et al. Spontaneous reactivation of herpes simplex virus type 1 in latently infected murine sensory ganglia. J Virol. 2007; 81(20): 11069-11074.

[50] Bernstein DI, Harrison CJ, Jenski LJ, Myers MG, Stanberry LR. Cell-mediated immunologic responses and recurrent genital herpes in the Guinea pig. Effects of glycoprotein immunotherapy. J Immunol. 1991; 146(10): 3571-3577.

[51] Lund JM, Linehan MM, Iijima N, Iwasaki A. Cutting edge: plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ. J Immunol. 2006; 177(11): 7510-7514.

[52] Bernstein DI, Cardin RD, Smith GA, et al. The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a Guinea pig model. NPJ Vaccines. 2020; 5(1): 104.

[53] Bernstein DI, Cardin RD, Bravo FJ, et al. Intranasal nanoemulsion-adjuvanted HSV-2 subunit vaccine is effective as a prophylactic and therapeutic vaccine using the Guinea pig model of genital herpes. Vaccine. 2019; 37(43): 6470-6477.

[54] Odegard JM, Flynn PA, Campbell DJ, et al. A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and Guinea pigs. Vaccine. 2016; 34(1): 101-109.

[55] Burn Aschner C, Knipe DM, Herold BC. Model of vaccine efficacy against HSV-2 superinfection of HSV-1 seropositive mice demonstrates protection by antibodies mediating cellular cytotoxicity. NPJ Vaccines. 2020; 5(1): 35.

[56] Scriba M. Recurrent genital herpes simplex virus (HSV) infection of Guinea pigs. Med Microbiol Immunol. 1976; 162(3-4): 201-208.

[57] Lukás B, Wiesendanger W, Schmidt-Ruppin KH. Herpes genitalis in Guinea-pigs. I. Kinetic study in infection with herpesvirus hominis type 2. Arch Virol. 1975; 41(1): 1-11.

[58] Stanberry LR, Kern ER, Richards JT, Abbott TM, Overall JC. Genital herpes in Guinea pigs: pathogenesis of the primary infection and description of recurrent disease. J Infect Dis. 1982; 146(3): 397-404.

[59] Stanberry LR, Harrison CJ, Bravo FJ, Childs F, Reece AL, Bernstein DI. Recurrent genital herpes in the Guinea pig augmented by ultraviolet irradiation: effects of treatment with acyclovir. Antivir Res. 1990; 13(5): 227-235.

[60] Bernstein DI, Ireland J, Bourne N. Pathogenesis of acyclovir-resistant herpes simplex type 2 isolates in animal models of genital herpes: models for antiviral evaluations. Antivir Res. 2000; 47(3): 159-169.

[61] Bernstein DI, Harrison CJ, Tomai MA, Miller RL. Daily or weekly therapy with resiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected Guinea pigs during and after treatment. J Infect Dis. 2001; 183(6): 844-849.

[62] Richards JT, Katz ME, Kern ER. Topical butylated hydroxytoluene treatment of genital herpes simplex virus infections of Guinea pigs. Antivir Res. 1985; 5(5): 281-290.

[63] Baumeister J, Fischer R, Eckenberg P, Henninger K, Ruebsamen-Waigmann H, Kleymann G. Superior efficacy of helicase-primase inhibitor BAY 57-1293 for herpes infection and latency in the Guinea pig model of human genital herpes disease. Antivir Chem Chemother. 2007; 18(1): 35-48.

[64] Bernstein DI. Use of the Guinea pig model of genital herpes to evaluate vaccines and antivirals: review. Antivir Res. 2020; 180: 104821.

[65] Kayesh MEH, Sanada T, Kohara M, Tsukiyama-Kohara K. Tree shrew as an emerging small animal model for human viral infection: a recent overview. Viruses. 2021; 13(8): 1641.

[66] Dasgupta G, BenMohamed L. Of mice and not humans: how reliable are animal models for evaluation of herpes CD8(+)-T cell-epitopes-based immunotherapeutic vaccine candidates? Vaccine. 2011; 29(35): 5824-5836.

[67] Fan Y, Huang ZY, Cao CC, et al. Genome of the Chinese tree shrew. Nat Commun. 2013; 4: 1426.

[68] Darai G, Zöller L, Matz B, Schwaier A, Flügel RM, Munk K. Experimental infection and the state of viral latency of adult tupaia with herpes simplex virus type 1 and 2 and infection of juvenile Tupaia with temperature-sensitive mutants of HSV type 2. Arch Virol. 1980; 65(3-4): 311-318.

[69] Darai G, Schwaier A, Komitowski D, Munk K. Experimental infection of Tupaia belangeri (tree shrews) with herpes simplex virus types 1 and 2. J Infect Dis. 1978; 137(3): 221-226.

[70] Darai G, Rösen A, Scholz J, Gelderblom H. Induction of generalized and lethal herpesvirus infection in the tree shrew by intrahepatic transfection of herpes simplex virus DNA. J Virol Methods. 1983; 7(5-6): 305-314.

[71] Rösen-Wolff A, Scholz J, Darai G. Organotropism of latent herpes simplex virus type 1 is correlated to the presence of a 1.5 kb RNA transcript mapped within the BamHI DNA fragment B (0.738 to 0.809 map units). Virus Res. 1989; 12(1): 43-51.

[72] Li L, Li Z, Wang E, et al. Herpes simplex virus 1 infection of tree shrews differs from that of mice in the severity of acute infection and viral transcription in the peripheral nervous system. J Virol. 2016; 90(2): 790-804.

[73] Depledge DP, Sadaoka T, Ouwendijk WJD. Molecular aspects of varicella-zoster virus latency. Viruses. 2018; 10(7): 349.

[74] Zerboni L, Sen N, Oliver SL, Arvin AM. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol. 2014; 12(3): 197-210.

[75] Ku CC, Zerboni L, Ito H, Graham BS, Wallace M, Arvin AM. Varicella-zoster virus transfer to skin by T cells and modulation of viral replication by epidermal cell interferon-alpha. J Exp Med. 2004; 200(7): 917-925.

[76] Ku CC, Padilla JA, Grose C, Butcher EC, Arvin AM. Tropism of varicella-zoster virus for human tonsillar CD4(+) T lymphocytes that express activation, memory, and skin homing markers. J Virol. 2002; 76(22): 11425-11433.

[77] Patil A, Goldust M, Wollina U. Herpes zoster: a review of clinical manifestations and management. Viruses. 2022; 14(2): 192.

[78] Arvin AM. Varicella-zoster virus. Clin Microbiol Rev. 1996; 9(3): 361-381.

[79] Forbes HJ, Bhaskaran K, Thomas SL, Smeeth L, Clayton T, Langan SM. Quantification of risk factors for herpes zoster: population based case-control study. BMJ (Clinical Research Ed). 2014; 348: g2911.

[80] Myers MG, Stanberry LR, Edmond BJ. Varicella-zoster virus infection of strain 2 Guinea pigs. J Infect Dis. 1985; 151(1): 106-113.

[81] Messaoudi I, Barron A, Wellish M, et al. Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans. PLoS Pathog. 2009; 5(11): e1000657.

[82] Traina-Dorge V, Doyle-Meyers LA, Sanford R, et al. Simian varicella virus is present in macrophages, dendritic cells, and T cells in lymph nodes of rhesus macaques after experimental reactivation. J Virol. 2015; 89(19): 9817-9824.

[83] Ouwendijk WJ, van den Ham HJ, Delany MW, et al. Alveolar barrier disruption in varicella pneumonia is associated with neutrophil extracellular trap formation. JCI Insight. 2020; 5(21): e138900.

[84] Langhoff E, Siegel RE. Pneumonitis in human cytomegalovirus infection. Curr Infect Dis Rep. 2006; 8(3): 222-230.

[85] Wroblewska Z, Valyi-Nagy T, Otte J, et al. A mouse model for varicella-zoster virus latency. Microb Pathog. 1993; 15(2): 141-151.

[86] Zerboni L, Ku CC, Jones CD, Zehnder JL, Arvin AM. Varicella-zoster virus infection of human dorsal root ganglia in vivo. Proc Natl Acad Sci USA. 2005; 102(18): 6490-6495.

[87] Moffat JF, Stein MD, Kaneshima H, Arvin AM. Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice. J Virol. 1995; 69(9): 5236-5242.

[88] Reichelt M, Zerboni L, Arvin AM. Mechanisms of varicella-zoster virus neuropathogenesis in human dorsal root ganglia. J Virol. 2008; 82(8): 3971-3983.

[89] Laemmle L, Goldstein RS, Kinchington PR. Modeling varicella zoster virus persistence and reactivation—closer to resolving a perplexing persistent state. Front Microbiol. 2019; 10: 1634.

[90] Myers MG, Duer HL, Hausler CK. Experimental infection of Guinea pigs with varicella-zoster virus. J Infect Dis. 1980; 142(3): 414-420.

[91] Matsunaga Y, Yamanishi K, Takahashi M. Experimental infection and immune response of Guinea pigs with varicella-zoster virus. Infect Immun. 1982; 37(2): 407-412.

[92] Pavan-Langston D, Dunkel EC. Ocular varicella-zoster virus infection in the Guinea pig. A new in vivo model. Arch Ophthalmol (Chicago, Ill: 1960). 1989; 107(7): 1068-1072.

[93] Jenski L, Myers MG. Cell-mediated immunity to varicella-zoster virus infection in strain 2 Guinea pigs. J Med Virol. 1987; 23(1): 23-30.

[94] Lowry PW, Solem S, Watson BN, et al. Immunity in strain 2 Guinea-pigs inoculated with vaccinia virus recombinants expressing varicella-zoster virus glycoproteins I, IV, V or the protein product of the immediate early gene 62. J Gen Virol. 1992; 73(pt 4): 811-819.

[95] Sabella C, Lowry PW, Abbruzzi GM, et al. Immunization with the immediate-early tegument protein (open reading frame 62) of varicella-zoster virus protects Guinea pigs against virus challenge. J Virol. 1993; 67(12): 7673-7676.

[96] Chen JJ, Gershon AA, Li ZS, Lungu O, Gershon MD. Latent and lytic infection of isolated Guinea pig enteric ganglia by varicella zoster virus. J Med Virol. 2003; 70(suppl 1): S71-S78.

[97] Chen JJ, Gershon AA, Li Z, Cowles RA, Gershon MD. Varicella zoster virus (VZV) infects and establishes latency in enteric neurons. J Neurovirol. 2011; 17(6): 578-589.

[98] Masood I, Majid Z, Rind W, Zia A, Riaz H, Raza S. Herpes Zoster-Induced Ogilvie's Syndrome. Case Rep Surg. 2015; 2015(2015): 563659.

[99] Nomdedéu JF, Nomdedéu J, Martino R, et al. Ogilvie's syndrome from disseminated varicella-zoster infection and infarcted celiac ganglia. J Clin Gastroenterol. 1995; 20(2): 157-159.

[100] Cheng X, Liu S, Sun J, et al. A synergistic lipid nanoparticle encapsulating mRNA shingles vaccine induces potent immune responses and protects Guinea pigs from viral challenges. Adv Mater (Deerfield Beach, FL). 2024; 36(13): e2310886.

[101] Debrus S, Sadzot-Delvaux C, Nikkels AF, Piette J, Rentier B. Varicella-zoster virus gene 63 encodes an immediate-early protein that is abundantly expressed during latency. J Virol. 1995; 69(5): 3240-3245.

[102] Wollina U, Machetanz J. Herpes zoster and postherpetic neuralgia. Hautarzt. 2016; 67(8): 653-665.

[103] Fleetwood-Walker SM, Quinn JP, Wallace C, et al. Behavioural changes in the rat following infection with varicella-zoster virus. J Gen Virol. 1999; 80(Pt 9): 2433-2436.

[104] Dalziel RG, Bingham S, Sutton D, et al. Allodynia in rats infected with varicella zoster virus--a small animal model for post-herpetic neuralgia. Brain Res Brain Res Rev. 2004; 46(2): 234-242.

[105] Sorel O, Messaoudi I. Varicella virus-host interactions during latency and reactivation: lessons from simian varicella virus. Front Microbiol. 2018; 9: 3170.

[106] Muneshige H, Toda K, Kimura H, Asou T. Does a viral infection cause complex regional pain syndrome? Acupunct Electrother Res. 2003; 28(3-4): 183-192.

[107] Theobald SJ, Khailaie S, Meyer-Hermann M, et al. Signatures of T and B cell development, functional responses and PD-1 upregulation after HCMV latent infections and reactivations in nod.RagGamma Mice Humanized with Cord Blood CD34(+) Cells. Front Immunol. 2018; 9: 2734.

[108] Ssentongo P, Hehnly C, Birungi P, et al. Congenital cytomegalovirus infection burden and epidemiologic risk factors in countries with universal screening: a systematic review and meta-analysis. JAMA Netw Open. 2021; 4(8): e2120736.

[109] Yue Y, Kaur A, Zhou SS, Barry PA. Characterization and immunological analysis of the rhesus cytomegalovirus homologue (Rh112) of the human cytomegalovirus UL83 lower matrix phosphoprotein (pp65). J Gen Virol. 2006; 87(pt 4): 777-787.

[110] Itell HL, Kaur A, Deere JD, Barry PA, Permar SR. Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections. Curr Opin Virol. 2017; 25: 126-133.

[111] Pitcher CJ, Hagen SI, Walker JM, et al. Development and homeostasis of T cell memory in rhesus macaque. J Immunol. 2002; 168(1): 29-43.

[112] Barry PA, Lockridge KM, Salamat S, et al. Nonhuman primate models of intrauterine cytomegalovirus infection. ILAR J. 2006; 47(1): 49-64.

[113] Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev. 2009; 22(1): 99-126.

[114] Woolf NK, Jaquish DV, Koehrn FJ. Transplacental murine cytomegalovirus infection in the brain of SCID mice. Virol J. 2007; 4: 26.

[115] Griffiths PD, Walter S. Cytomegalovirus. Curr Opin Infect Dis. 2005; 18(3): 241-245.

[116] Roback JD, Su L, Newman JL, Saakadze N, Lezhava LJ, Hillyer CD. Transfusion-transmitted cytomegalovirus (CMV) infections in a murine model: characterization of CMV-infected donor mice. Transfusion. 2006; 46(6): 889-895.

[117] Krstanović F, Britt WJ, Jonjić S, Brizić I. Cytomegalovirus infection and inflammation in developing brain. Viruses. 2021; 13(6): 1078.

[118] Craighead JE, Martin WB, Huber SA. Role of CD4+ (helper) T cells in the pathogenesis of murine cytomegalovirus myocarditis. Lab Investig. 1992; 66(6): 755-761.

[119] Shellam GR, Flexman JP, Farrell HE, Papadimitriou JM. The genetic background modulates the effect of the beige gene on susceptibility to cytomegalovirus infection in mice. Scand J Immunol. 1985; 22(2): 147-155.

[120] Medearis DN. Mouse cytomegalovirus infection. 3. Attempts to produce intrauterine infections. Am J Hyg. 1964; 80: 113-120.

[121] Dagna L, Pritchett JC, Lusso P. Immunomodulation and immunosuppression by human herpesvirus 6A and 6B. Future Virol. 2013; 8(3): 273-287.

[122] Crawford LB, Tempel R, Streblow DN, et al. Human cytomegalovirus induces cellular and humoral virus-specific immune responses in humanized BLT mice. Sci Rep. 2017; 7(1): 937.

[123] Caposio P, van den Worm S, Crawford L, et al. Characterization of a live-attenuated HCMV-based vaccine platform. Sci Rep. 2019; 9(1): 19236.

[124] Wahl A, De C, Abad Fernandez M, et al. Precision mouse models with expanded tropism for human pathogens. Nat Biotechnol. 2019; 37(10): 1163-1173.

[125] Roark HK, Jenks JA, Permar SR, Schleiss MR. Animal models of congenital cytomegalovirus transmission: implications for vaccine development. J Infect Dis. 2020; 221(suppl 1): S60-S73.

[126] Schleiss MR, McAllister S, Armién AG, et al. Molecular and biological characterization of a new isolate of Guinea pig cytomegalovirus. Viruses. 2014; 6(2): 448-475.

[127] Schleiss MR. Animal models of congenital cytomegalovirus infection: an overview of progress in the characterization of Guinea pig cytomegalovirus (GPCMV). J Clin Virol. 2002; 25(suppl 2): S37-S49.

[128] Yamada S, Katano H, Sato Y, Fukuchi S, Hashimoto K, Inoue N. An ex vivo culture model for placental cytomegalovirus infection using slices of Guinea pig placental tissue. Placenta. 2016; 37: 85-88.

[129] Schleiss MR. Nonprimate models of congenital cytomegalovirus (CMV) infection: gaining insight into pathogenesis and prevention of disease in newborns. ILAR J. 2006; 47(1): 65-72.

[130] Woolf NK. Guinea pig model of congenital CMV-induced hearing loss: a review. Transplant Proc. 1991; 23(3 Suppl 3): 32-34, discussion 34.

[131] Woolf NK, Koehrn FJ, Harris JP, Richman DD. Congenital cytomegalovirus labyrinthitis and sensorineural hearing loss in Guinea pigs. J Infect Dis. 1989; 160(6): 929-937.

[132] Park AH, Gifford T, Schleiss MR, et al. Development of cytomegalovirus-mediated sensorineural hearing loss in a Guinea pig model. Arch Otolaryngol Head Neck Surg. 2010; 136(1): 48-53.

[133] Schleiss MR, McGregor A, Choi KY, Date SV, Cui X, McVoy MA. Analysis of the nucleotide sequence of the Guinea pig cytomegalovirus (GPCMV) genome. Virol J. 2008; 5: 139.

[134] Schleiss MR, Bourne N, Bernstein DI. Preconception vaccination with a glycoprotein B (gB) DNA vaccine protects against cytomegalovirus (CMV) transmission in the Guinea pig model of congenital CMV infection. J Infect Dis. 2003; 188(12): 1868-1874.

[135] Schleiss MR, Choi KY, Anderson J, et al. Glycoprotein B (gB) vaccines adjuvanted with AS01 or AS02 protect female Guinea pigs against cytomegalovirus (CMV) viremia and offspring mortality in a CMV-challenge model. Vaccine. 2014; 32(23): 2756-2762.

[136] Choi KY, El-Hamdi NS, McGregor A. Neutralizing antibodies to gB based CMV vaccine requires full length antigen but reduced virus neutralization on non-fibroblast cells limits vaccine efficacy in the Guinea pig model. Vaccine. 2020; 38(10): 2340-2349.

[137] Kern ER. Pivotal role of animal models in the development of new therapies for cytomegalovirus infections. Antivir Res. 2006; 71(2-3): 164-171.

[138] Estes JD, Wong SW, Brenchley JM. Nonhuman primate models of human viral infections. Nat Rev Immunol. 2018; 18(6): 390-404.

[139] Lieberman PM. Virology. Epstein-Barr virus turns 50. Science (New York, NY). 2014; 343(6177): 1323-1325.

[140] Sun L, Che K, Zhao Z, Liu S, Xing X, Luo B. Sequence analysis of Epstein-Barr virus (EBV) early genes BARF1 and BHRF1 in NK/T cell lymphoma from northern China. Virol J. 2015; 12: 135.

[141] Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med. 2002; 8(6): 594-599.

[142] Jenson HB. Epstein-Barr virus. Pediatr Rev. 2011; 32(9): 375-383; quiz 384.

[143] Shannon-Lowe C, Rickinson AB, Bell AI. Epstein-Barr virus-associated lymphomas. Philos Trans R Soc Lond Ser B Biol Sci. 2017; 372(1732): 20160271.

[144] Dunmire SK, Verghese PS, Balfour HH. Primary Epstein-Barr virus infection. J Clin Virol. 2018; 102: 84-92.

[145] Takashima K, Ohashi M, Kitamura Y, et al. A new animal model for primary and persistent Epstein-Barr virus infection: human EBV-infected rabbit characteristics determined using sequential imaging and pathological analysis. J Med Virol. 2008; 80(3): 455-466.

[146] Fujiwara S, Nakamura H. Animal models for Gammaherpesvirus infections: recent development in the analysis of virus-induced pathogenesis. Pathogens Basel. 2020; 9(2): 116.

[147] Niedobitek G, Agathanggelou A, Finerty S, et al. Latent Epstein-Barr virus infection in cottontop tamarins. A possible model for Epstein-Barr virus infection in humans. Am J Pathol. 1994; 145(4): 969-978.

[148] Cleary ML, Epstein MA, Finerty S, et al. Individual tumors of multifocal EB virus-induced malignant lymphomas in tamarins arise from different B-cell clones. Science. 1985; 228(4700): 722-724.

[149] Moutschen M, Léonard P, Sokal EM, et al. Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults. Vaccine. 2007; 25(24): 4697-4705.

[150] Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2007; 196(12): 1749-1753.

[151] HWt V, Latreille P, Wamsley P, et al. Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol. 1997; 71(8): 5894-5904.

[152] Terry LA, Stewart JP, Nash AA, Fazakerley JK. Murine gammaherpesvirus-68 infection of and persistence in the central nervous system. J Gen Virol. 2000; 81(Pt 11): 2635-2643.

[153] Sunil-Chandra NP, Efstathiou S, Nash AA. Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. J Gen Virol. 1992; 73(pt 12): 3275-3279.

[154] Häusler M, Sellhaus B, Scheithauer S, et al. Murine gammaherpesvirus-68 infection of mice: a new model for human cerebral Epstein-Barr virus infection. Ann Neurol. 2005; 57(4): 600-603.

[155] Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988; 335(6187): 256-259.

[156] Ma SD, Hegde S, Young KH, et al. A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J Virol. 2011; 85(1): 165-177.

[157] Hartlage AS, Liu T, Patton JT, et al. The Epstein-Barr virus lytic protein BZLF1 as a candidate target antigen for vaccine development. Cancer Immunol Res. 2015; 3(7): 787-794.

[158] Sun C, Kang YF, Fang XY, et al. A gB nanoparticle vaccine elicits a protective neutralizing antibody response against EBV. Cell Host Microbe. 2023; 31(11): 1882-1897.e10.

[159] Wang Z, Yi X, Du L, et al. A study of Epstein-Barr virus infection in the Chinese tree shrew(Tupaia belangeri chinensis). Virol J. 2017; 14(1): 193.

[160] Xia W, Chen H, Feng Y, et al. Tree shrew is a suitable animal model for the study of Epstein Barr virus. Front Immunol. 2021; 12: 789604.

[161] He M, Cheng F, da Silva SR, et al. Molecular biology of KSHV in relation to HIV/AIDS-associated oncogenesis. Cancer Treat Res. 2019; 177: 23-62.

[162] Cai Q, Verma SC, Lu J, Robertson ES. Molecular biology of Kaposi's sarcoma-associated herpesvirus and related oncogenesis. Adv Virus Res. 2010; 78: 87-142.

[163] Ganem D. KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest. 2010; 120(4): 939-949.

[164] Schulz TF. KSHV (HHV8) infection. J Infect. 2000; 41(2): 125-129.

[165] Purushothaman P, Dabral P, Gupta N, Sarkar R, Verma SC. KSHV genome replication and maintenance. Front Microbiol. 2016; 7: 54.

[166] Fujiwara S. Animal models of human Gammaherpesvirus infections. Adv Exp Med Biol. 2018; 1045: 413-436.

[167] Desrosiers RC, Sasseville VG, Czajak SC, et al. A herpesvirus of rhesus monkeys related to the human Kaposi's sarcoma-associated herpesvirus. J Virol. 1997; 71(12): 9764-9769.

[168] Wong SW, Bergquam EP, Swanson RM, et al. Induction of B cell hyperplasia in simian immunodeficiency virus-infected rhesus macaques with the simian homologue of Kaposi's sarcoma-associated herpesvirus. J Exp Med. 1999; 190(6): 827-840.

[169] Orzechowska BU, Powers MF, Sprague J, et al. Rhesus macaque rhadinovirus-associated non-Hodgkin lymphoma: animal model for KSHV-associated malignancies. Blood. 2008; 112(10): 4227-4234.

[170] Chang H, Wachtman LM, Pearson CB, et al. Non-human primate model of Kaposi's sarcoma-associated herpesvirus infection. PLoS Pathog. 2009; 5(10): e1000606.

[171] Dittmer DP, Damania B, Sin SH. Animal models of tumorigenic herpesviruses--an update. Curr Opin Virol. 2015; 14: 145-150.

[172] Sewatanon J, Liu H, Ling PD. Promyelocytic leukemia protein modulates establishment and maintenance of latent gammaherpesvirus infection in peritoneal cells. J Virol. 2013; 87(22): 12151-12157.

[173] Barton E, Mandal P, Speck SH. Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol. 2011; 29: 351-397.

[174] Cieniewicz B, Dong Q, Li G, et al. Murine Gammaherpesvirus 68 pathogenesis is independent of Caspase-1 and Caspase-11 in mice and impairs interleukin-1β production upon extrinsic stimulation in culture. J Virol. 2015; 89(13): 6562-6574.

[175] Bravo Cruz AG, Damania B. In vivo models of oncoproteins encoded by Kaposi's sarcoma-associated herpesvirus. J Virol. 2019; 93(11): e01053-18.

[176] Mutlu AD, Cavallin LE, Vincent L, et al. In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma. Cancer Cell. 2007; 11(3): 245-258.

[177] An FQ, Folarin HM, Compitello N, et al. Long-term-infected telomerase-immortalized endothelial cells: a model for Kaposi's sarcoma-associated herpesvirus latency in vitro and in vivo. J Virol. 2006; 80(10): 4833-4846.

[178] Foreman KE, Friborg J, Chandran B, et al. Injection of human herpesvirus-8 in human skin engrafted on SCID mice induces Kaposi's sarcoma-like lesions. J Dermatol Sci. 2001; 26(3): 182-193.

[179] Parsons CH, Adang LA, Overdevest J, et al. KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice. J Clin Invest. 2006; 116(7): 1963-1973.

[180] Wu W, Vieira J, Fiore N, et al. KSHV/HHV-8 infection of human hematopoietic progenitor (CD34+) cells: persistence of infection during hematopoiesis in vitro and in vivo. Blood. 2006; 108(1): 141-151.

[181] Dai L, Trillo-Tinoco J, Bai L, et al. Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL). PLoS One. 2014; 9(2): e90349.

[182] Wang LX, Kang G, Kumar P, et al. Humanized-BLT mouse model of Kaposi's sarcoma-associated herpesvirus infection. Proc Natl Acad Sci USA. 2014; 111(8): 3146-3151.

[183] Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis. 1998; 26(3): 541-553; quiz 554-5.

[184] Wan M, Yang X, Sun J, et al. An adenovirus-based recombinant herpes simplex virus 2 (HSV-2) therapeutic vaccine is highly protective against acute and recurrent HSV-2 disease in a Guinea pig model. Viruses. 2023; 15(1): 219.

[185] Ouwendijk WJ, Verjans GM. Pathogenesis of varicelloviruses in primates. J Pathol. 2015; 235(2): 298-311.

[186] Mahalingam R, Gershon A, Gershon M, et al. Current in vivo models of varicella-zoster virus neurotropism. Viruses. 2019; 11(6): 502.

[187] Zerboni L, Sung P, Lee G, Arvin A. Age-associated differences in infection of human skin in the SCID mouse model of varicella-zoster virus pathogenesis. J Virol. 2018; 92(11): e00002-18.

[188] Johannessen I, Crawford DH. In vivo models for Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (BLPD). Revi Med Virol. 1999; 9(4): 263-277.

[189] Young LS, Finerty S, Brooks L, Scullion F, Rickinson AB, Morgan AJ. Epstein-Barr virus gene expression in malignant lymphomas induced by experimental virus infection of cottontop tamarins. J Virol. 1989; 63(5): 1967-1974.

[190] Shope T, Dechairo D, Miller G. Malignant lymphoma in cottontop marmosets after inoculation with Epstein-Barr virus. Proc Natl Acad Sci USA. 1973; 70(9): 2487-2491.

[191] Hayashi K, Teramoto N, Akagi T. Animal in vivo models of EBV-associated lymphoproliferative diseases: special references to rabbit models. Histol Histopathol. 2002; 17(4): 1293-1310.

[192] Khan G, Ahmed W, Philip PS, Ali MH, Adem A. Healthy rabbits are susceptible to Epstein-Barr virus infection and infected cells proliferate in immunosuppressed animals. Virol J. 2015; 12: 28.

[193] Fujiwara S, Imadome K, Takei M. Modeling EBV infection and pathogenesis in new-generation humanized mice. Exp Mol Med. 2015; 47(1): e135.

[194] Traggiai E, Chicha L, Mazzucchelli L, et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004; 304(5667): 104-107.

[195] Strowig T, Gurer C, Ploss A, et al. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med. 2009; 206(6): 1423-1434.

[196] Lee EK, Joo EH, Song KA, et al. Effects of lymphocyte profile on development of EBV-induced lymphoma subtypes in humanized mice. Proc Natl Acad Sci USA. 2015; 112(42): 13081-13086.

[197] Sunil-Chandra NP, Arno J, Fazakerley J, Nash AA. Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. Am J Pathol. 1994; 145(4): 818-826.

[198] Dubich T, Lieske A, Santag S, et al. An endothelial cell line infected by Kaposi's sarcoma-associated herpes virus (KSHV) allows the investigation of Kaposi's sarcoma and the validation of novel viral inhibitors in vitro and in vivo. J Mol Med (Berl). 2019; 97(3): 311-324.

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