{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T21:53:45Z","timestamp":1793656425095,"version":"4.5.1"},"reference-count":59,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T00:00:00Z","timestamp":1577059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital infections and central nervous system infections. CMV infections are difficult to treat due to their specific life cycles, mutation, and latency characteristic. Despite recent advances, current drugs used for treating active CMV infections are limited in their efficacy, and the eradication of latent infections is impossible. Current antiviral agents which target the UL54 DNA polymerase are restricted because of nephrotoxicity and viral resistance. CMV also cannot be prevented or eliminated with a vaccine. Fortunately, letermovir which targets the human CMV (HCMV) terminase complex has been recently approved to treat CMV infections in humans. The growing point is developing antiviral agents against both lytically and latently infected cells. The nucleic acid-based therapeutic approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)\/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being explored to remove acute and\/or latent CMV infections. HCMV vaccine is being developed for prophylaxis. Additionally, adoptive T cell therapy (ACT) has been experimentally used to combate drug-resistant and recurrent CMV in patients after cell and\/or organ transplantation. Developing antiviral agents is promising in this area to obtain fruitful outcomes and to have a great impact on humans for the therapy of CMV infections.<\/jats:p>","DOI":"10.3390\/v12010021","type":"journal-article","created":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T05:56:15Z","timestamp":1577166975000},"page":"21","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Antiviral Agents as Therapeutic Strategies Against Cytomegalovirus Infections"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-527X","authenticated-orcid":false,"given":"Shiu-Jau","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Mackay Memorial Hospital, Taipei 10491, Taiwan"},{"name":"Department of Medicine, Mackay Medicine College, Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-5338","authenticated-orcid":false,"given":"Shao-Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Jianan Psychiatric Center, Ministry of Health and Welfare, Tainan 71742, Taiwan"},{"name":"Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6592-2845","authenticated-orcid":false,"given":"Yuan-Chuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Program in Comparative Biochemistry, University of California, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s00705-012-1299-6","article-title":"Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses","volume":"157","author":"Adams","year":"2012","journal-title":"Arch. Virol."},{"key":"ref_2","unstructured":"Murray, P.R., Rosenthal, K.S., and Pfaller, M.A. (2005). Medical Microbiology, Elsevier Mosby. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7411","DOI":"10.1128\/JVI.74.16.7411-7421.2000","article-title":"Construction and characterization of murine cytomegaloviruses that contain transposon insertions at open reading frames m09 and M83","volume":"74","author":"Zhan","year":"2000","journal-title":"J. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S111","DOI":"10.1016\/S1386-6532(02)00096-3","article-title":"Genetic analyses of gene function and pathogenesis of murine cytomegalovirus by transposon-mediated mutagenesis","volume":"25","author":"Lee","year":"2002","journal-title":"J. Clin Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14223","DOI":"10.1073\/pnas.2334032100","article-title":"Functional profiling of a human cytomegalovirus genome","volume":"100","author":"Dunn","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0166-3542(01)00126-7","article-title":"Inhibition of cytomegalovirus immediate early gene expression: A therapeutic option?","volume":"49","author":"Scholz","year":"2001","journal-title":"Antivir. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1128\/AAC.44.6.1588-1597.2000","article-title":"Recombinant green fluorescent protein-expressing human cytomegalovirus as a tool for screening antiviral agents","volume":"44","author":"Marschall","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"La, Y., Kwon, D.E., Yoo, S.G., Lee, K.H., Han, S.H., and Song, Y.G. (2019). Human cytomegalovirus seroprevalence and titers in solid organ transplant recipients and transplant donors in Seoul, South Korea. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4607-x"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.yexmp.2011.10.011","article-title":"Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: Cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship","volume":"92","author":"Melnick","year":"2012","journal-title":"Exp. Mol. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1042\/bj2410313","article-title":"Molecular biology and immunology of cytomegalovirus","volume":"241","author":"Griffiths","year":"1987","journal-title":"Biochem. J."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Crough, T., and Khanna, R. (2009). Immunobiology of human cytomegalovirus: From bench to bedside. Clin. Microbiol. Rev., 76\u201398.","DOI":"10.1128\/CMR.00034-08"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chen, Y.-C., Sheng, J., Trang, P., and Liu, F. (2018). Potential application of the CRISPR\/Cas9 system against herpesvirus infections. Viruses, 10.","DOI":"10.3390\/v10060291"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/ki.1985.218","article-title":"Reactivation of latent murine cytomegalovirus from kidney","volume":"28","author":"Porter","year":"1985","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/rmv.1862","article-title":"Cytomegalovirus latency and reactivation: Recent insights into an old age problem","volume":"26","author":"Dupont","year":"2016","journal-title":"Rev. Med. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1001\/jama.289.8.1008","article-title":"Maternal immunity and prevention of congenital cytomegalovirus infection","volume":"289","author":"Fowler","year":"2003","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"297-e1","DOI":"10.1016\/j.ajog.2009.11.018","article-title":"Human cytomegalovirus reinfection is associated with intrauterine transmission in a highly cytomegalovirus-immune maternal population","volume":"202","author":"Yamamoto","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/rmv.544","article-title":"New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection","volume":"17","author":"Dollard","year":"2007","journal-title":"Rev. Med. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/rmv.535","article-title":"Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection","volume":"17","author":"Kenneson","year":"2007","journal-title":"Rev. Med. Virol."},{"key":"ref_19","first-page":"23","article-title":"Prevention of maternal cytomegalovirus infection: Current status and future prospects","volume":"2","author":"Nyholm","year":"2010","journal-title":"Int. J. Women\u2019s Health"},{"key":"ref_20","first-page":"213","article-title":"Congenital cytomegalovirus infection","volume":"95","author":"Leung","year":"2003","journal-title":"J. Natl. Med. Assoc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.jpeds.2013.12.007","article-title":"Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection","volume":"164","author":"Dreher","year":"2014","journal-title":"J. Pediatrics"},{"key":"ref_22","first-page":"335","article-title":"Congenital cytomegalovirus infection: New prospects for prevention and therapy","volume":"60","author":"Swanson","year":"2013","journal-title":"Pediatric Clin."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1097\/INF.0b013e31822d9640","article-title":"Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population","volume":"30","author":"Yamamoto","year":"2011","journal-title":"Pediatric Infect. Dis. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jcv.2005.09.016","article-title":"Congenital cytomegalovirus (CMV) infection and hearing deficit","volume":"35","author":"Fowler","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S178","DOI":"10.1093\/cid\/cit629","article-title":"Congenital cytomegalovirus infection: Clinical outcome","volume":"57","author":"Boppana","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1086\/600882","article-title":"Birth prevalence and natural history of congenital cytomegalovirus infection in a highly seroimmune population","volume":"49","author":"Yamamoto","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jcv.2005.09.015","article-title":"Congenital cytomegalovirus infection following first trimester maternal infection: Symptoms at birth and outcome","volume":"35","author":"Pass","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1093\/jac\/dkp083","article-title":"Treatment of congenital cytomegalovirus infection: Implications for future therapeutic strategies","volume":"63","author":"Nassetta","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/01.inf.0000199261.98769.29","article-title":"Multicity Italian study of congenital cytomegalovirus infection","volume":"25","author":"Barbi","year":"2006","journal-title":"Pediatric Infect. Dis. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1515\/JPM.2009.127","article-title":"Guidelines on CMV congenital infection","volume":"37","author":"Coll","year":"2009","journal-title":"J. Perinat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s11940-008-0020-2","article-title":"Congenital cytomegalovirus infection: Update on management strategies","volume":"10","author":"Schleiss","year":"2008","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jcv.2005.09.017","article-title":"Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss","volume":"35","author":"Nance","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.molmed.2011.07.003","article-title":"All is fair in virus\u2013host interactions: NK cells and cytomegalovirus","volume":"17","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_34","first-page":"173","article-title":"Natural killer cells and human cytomegalovirus","volume":"Volume 2","author":"Wilkinson","year":"2013","journal-title":"Cytomegaloviruses: From Molecular Biology to Intervention"},{"key":"ref_35","unstructured":"Reddehase, M.J. (2013). Innate immunity to cytomegalovirus in the murine model. Cytomegaloviruses from Molecular Pathogenesis to Intervention, Caister Academic Press."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Krishna, B.A., Wills, M.R., and Sinclair, J.H. (2019). Advances in the treatment of cytomegalovirus. Br. Med. Bull., ldz031.","DOI":"10.1093\/bmb\/ldz031"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jcv.2019.04.007","article-title":"New vaccines and antiviral drugs for cytomegalovirus","volume":"116","author":"Griffiths","year":"2019","journal-title":"J. Clin Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6877","DOI":"10.1523\/JNEUROSCI.0970-17.2017","article-title":"Valnoctamide Inhibits Cytomegalovirus Infection in Developing Brain and Attenuates Neurobehavioral Dysfunctions and Brain Abnormalities","volume":"37","author":"Ornaghi","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"ofz375","DOI":"10.1093\/ofid\/ofz375","article-title":"Emergence and persistence of letermovir-resistant cytomegalovirus in a patient with primary immunodeficiency","volume":"Volume 6","author":"Popping","year":"2019","journal-title":"Open Forum Infectious Diseases"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lin, A., Maloy, M., Su, Y., Bhatt, V., DeRespiris, L., Griffin, M., Lau, C., Proli, A., Barker, J., and Shaffer, B. (2019). Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience. Transpl. Infect. Dis, e13187.","DOI":"10.1111\/tid.13187"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Aryal, S., Katugaha, S.B., Cochrane, A., Brown, A.W., Nathan, S.D., Shlobin, O.A., Ahmad, K., Marinak, L., Chun, J., and Fregoso, M. (2019). Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients. Transpl Infect. Dis., e13166.","DOI":"10.1111\/tid.13166"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Veit, T., Munker, D., Kauke, T., Zoller, M., Michel, S., Ceelen, F., Schiopu, S., Barton, J., Arnold, P., and Milger, K. Letermovir for difficult to treat cytomegalovirus infection in lung transplant recipients. Transplantation, 2019.","DOI":"10.1055\/s-0039-3403384"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1056\/NEJMoa1309533","article-title":"Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation","volume":"370","author":"Chemaly","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1056\/NEJMoa1706640","article-title":"Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation","volume":"377","author":"Marty","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jcv.2015.11.033","article-title":"Persistent CMV infection after allogeneic hematopoietic stem cell transplantation in a CMV-seronegative donorto-positive recipient constellation: Development of multidrug resistance in the absence of anti-viral cellular immunity","volume":"74","author":"Herling","year":"2016","journal-title":"J. Clin Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1056\/NEJMoa1714656","article-title":"Maribavir for preemptive treatment of cytomegalovirus reactivation","volume":"381","author":"Maertens","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/cid\/ciy706","article-title":"Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: A randomized, dose-ranging, double-blind, phase 2 Study","volume":"68","author":"Papanicolaou","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1261\/rna.069682.118","article-title":"Inhibition of human cytomegalovirus major capsid protein expression and replication by ribonuclease P-associated external guide sequences","volume":"25","author":"Deng","year":"2019","journal-title":"RNA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.omtn.2017.10.007","article-title":"Inhibition of murine cytomegalovirus infection in animals by RNase P-associated external guide sequences","volume":"9","author":"Li","year":"2017","journal-title":"Mol. Nucleic Acids"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.virol.2019.01.021","article-title":"Editing the human cytomegalovirus genome with the CRISPR\/Cas9 system","volume":"529","author":"King","year":"2019","journal-title":"Virology"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gergen, J., Coulon, F., Creneguy, A., Elain-Duret, N., Gutierrez, A., Pinkenburg, O., Verhoeyen, E., Anegon, I., Nguyen, T.H., and Halary, F.A. (2018). Multiplex CRISPR\/Cas9 system impairs HCMV replication by excising an essential viral gene. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192602"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"van Diemen, F.R., Kruse, E.M., Hooykaas, M.J., Bruggeling, C.E., Sch\u00fcrch, A.C., van Ham, P.M., Imhof, S.M., Nijhuis, M., Wiertz, E.J., and Lebbink, R.J. (2016). CRISPR\/Cas9-mediated genome editing of herpesviruses limits productive and latent Infections. PloS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005701"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.1178811","article-title":"Breaking the code of DNA binding specificity of TAL-type III effectors","volume":"326","author":"Boch","year":"2009","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chen, S.J., and Chen, Y.C. (2019). Potential application of TALENs against murine cytomegalovirus latent infections. Viruses, 11.","DOI":"10.3390\/v11050414"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e01442","DOI":"10.1128\/JVI.01442-19","article-title":"Inclusion of the viral pentamer complex in a vaccine design greatly improves protection against congenital cytomegalovirus in the guinea pig model","volume":"93","author":"Choi","year":"2019","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Liu, Y., Freed, D.C., Li, L., Tang, A., Li, F., Murray, E.M., Adler, S.P., McVoy, M.A., Rupp, R.E., and Barrett, D. (2019). A replication defective human cytomegalovirus vaccine elicits humoral immune responses analogous to those with natural infection. J. Virol., JVI.00747\u2013JVI.00819.","DOI":"10.1128\/JVI.00747-19"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Fatic, A., Zhang, N., Keller, M.D., and Hanley, P.J. (2019). The pipeline of antiviral T-cell therapy: What\u2019s in the clinic and undergoing development. Transfusion.","DOI":"10.1111\/trf.15501"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Faist, B., Schlott, F., Stemberger, C., Dennehy, K.M., Krackhardt, A., Verbeek, M., Grigoleit, G.U., Schiemann, M., Hoffmann, D., and Dick, A. (2019). Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0223258"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.1172\/JCI128323","article-title":"T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response","volume":"129","author":"Smith","year":"2019","journal-title":"J. Clin Invest."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/1\/21\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:45:00Z","timestamp":1760190300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/1\/21"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,23]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["v12010021"],"URL":"https:\/\/doi.org\/10.3390\/v12010021","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,23]]}}}