{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:25:37Z","timestamp":1791822337421,"version":"4.3.4"},"reference-count":110,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370157"],"award-info":[{"award-number":["32370157"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pathogens"],"abstract":"<jats:p>Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations.<\/jats:p>","DOI":"10.3390\/pathogens14100998","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T16:18:33Z","timestamp":1759421913000},"page":"998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Immunoregulatory Mechanisms of Human Cytomegalovirus from Primary Infection to Reactivation"],"prefix":"10.3390","volume":"14","author":[{"given":"Xiaodan","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Interventional Diagnosis and Treatment Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-581X","authenticated-orcid":false,"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Room 1121, D5A Building, Chengdu Frontier Medical Science Center, No. 2222 Xinchuan Road, Chengdu 610213, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/eye.2011.327","article-title":"Cytomegalovirus and the eye","volume":"26","author":"Carmichael","year":"2012","journal-title":"Eye"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sunil-Chandra, N.P., Jayasundara, M., Gunathilaka, M., and Suminda, S.D.H. (2025). Human cytomegalovirus (HCMV) trends in Sri Lanka: Insights from a hospital-based seroprevalence analysis. BMC Infect. Dis., 25.","DOI":"10.1186\/s12879-025-10594-2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104508","DOI":"10.1016\/j.bjid.2025.104508","article-title":"Prevalence and investigation of Cytomegalovirus (HCMV) in blood donors from the main blood establishment in Rio de Janeiro\/Brazil","volume":"29","author":"Oliveira","year":"2025","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Radoi, C.L., Zlatian, O., Balasoiu, M., Dragomir, T.L., Sorop, M.I., Bagiu, I.C., Boeriu, E., Susan, M., Sorop, B., and Oprisoni, L.A. (2024). Seroprevalence of Anti-Cytomegalovirus Antibodies in Pregnant Women from South-West Romania. Microorganisms, 12.","DOI":"10.3390\/microorganisms12020268"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e29525","DOI":"10.1002\/jmv.29525","article-title":"Estimated cytomegalovirus seroprevalence in the general population of the United States and Canada","volume":"96","author":"Lally","year":"2024","journal-title":"J. Med. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"\u00c1lvarez-Heredia, P., Reina-Alfonso, I., Dom\u00ednguez-Del-Castillo, J.J., Hassouneh, F., Guti\u00e9rrez-Gonz\u00e1lez, C., Batista-Duharte, A., P\u00e9rez, A.B., Sarramea, F., Ja\u00e9n-Moreno, M.J., and Camacho-Rodr\u00edguez, C. (2023). Spanish HCMV Seroprevalence in the 21st Century. Viruses, 16.","DOI":"10.3390\/v16010006"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1007\/s10096-020-03814-x","article-title":"Thirty years of CMV seroprevalence-a longitudinal analysis in a German university hospital","volume":"39","author":"Hoehl","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s41182-024-00634-z","article-title":"Seroprevalence of cytomegalovirus among pregnant women in Singapore","volume":"52","author":"Partana","year":"2024","journal-title":"Trop. Med. Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13584-023-00566-9","article-title":"Cytomegalovirus (CMV) seroprevalence among women at childbearing age, maternal and congenital CMV infection: Policy implications of a descriptive, retrospective, community-based study","volume":"12","author":"Schlesinger","year":"2023","journal-title":"Isr. J. Health Policy Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Matthews, S.M., Groves, I.J., and O\u2019Connor, C.M. (2023). Chromatin control of human cytomegalovirus infection. mBio, 14.","DOI":"10.1128\/mbio.00326-23"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2147\/IJCTM.S115669","article-title":"Current strategies and future directions for the prevention of transfusion-transmitted cytomegalovirus","volume":"5","author":"Harmon","year":"2017","journal-title":"Int. J. Clin. Transfus. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/dc.20048","article-title":"Identification of cytomegalovirus in a liquid-based gynecologic sample using morphology, immunohistochemistry, and DNA real-time PCR detection","volume":"30","author":"Sekhon","year":"2004","journal-title":"Diagn. Cytopathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1083\/jcb.200604069","article-title":"Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA","volume":"174","author":"Poncet","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","unstructured":"Almishaal, A.A. (2022). Knowledge of cytomegalovirus infection among women in Saudi Arabia: A cross-sectional study. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0274863"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eadd1168","DOI":"10.1126\/sciadv.add1168","article-title":"Cytomegalovirus US28 regulates cellular EphA2 to maintain viral latency","volume":"8","author":"Wass","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/S1473-3099(04)01202-2","article-title":"Human cytomegalovirus: Clinical aspects, immune regulation, and emerging treatments","volume":"4","author":"Gandhi","year":"2004","journal-title":"Lancet Infect. Dis."},{"key":"ref_18","first-page":"249","article-title":"CMV-induced Hearing Loss","volume":"2","author":"Singh","year":"2023","journal-title":"Newborn"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1080\/00365540802308431","article-title":"Congenital CMV infection: Prevalence in newborns and the impact on hearing deficit","volume":"40","author":"Engman","year":"2008","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_20","first-page":"e45634","article-title":"Cytomegalovirus Esophagitis in an Immunocompromised Patient","volume":"15","author":"Ali","year":"2023","journal-title":"Cureus"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1099\/jgv.0.001327","article-title":"A novel murine model of differentiation-mediated cytomegalovirus reactivation from latently infected bone marrow haematopoietic cells","volume":"100","author":"Liu","year":"2019","journal-title":"J. Gen. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Buehler, J., Carpenter, E., Zeltzer, S., Igarashi, S., Rak, M., Mikell, I., Nelson, J.A., and Goodrum, F. (2019). Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency. PLoS Pathog., 15.","DOI":"10.1101\/648543"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jackson, S.E., Sedikides, G.X., Okecha, G., Poole, E.L., Sinclair, J.H., and Wills, M.R. (2017). Latent Cytomegalovirus (CMV) Infection Does Not Detrimentally Alter T Cell Responses in the Healthy Old, But Increased Latent CMV Carriage Is Related to Expanded CMV-Specific T Cells. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00733"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"d1575","DOI":"10.2741\/jarvis","article-title":"Mechanisms of human cytomegalovirus persistence and latency","volume":"7","author":"Jarvis","year":"2002","journal-title":"Front. Biosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41564-018-0131-9","article-title":"Human cytomegalovirus reprogrammes haematopoietic progenitor cells into immunosuppressive monocytes to achieve latency","volume":"3","author":"Zhu","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Nikitina, E., Larionova, I., Choinzonov, E., and Kzhyshkowska, J. (2018). Monocytes and Macrophages as Viral Targets and Reservoirs. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092821"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22","DOI":"10.17116\/patol201577222-27","article-title":"Postmortem diagnosis of influenza during its epidemic and interepidemic periods","volume":"77","author":"Gladkov","year":"2015","journal-title":"Arkhiv Patologii"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5914","DOI":"10.4049\/jimmunol.0900255","article-title":"Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response","volume":"184","author":"Hoarau","year":"2010","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/pros.23163","article-title":"Human herpesvirus 8 establishes a latent infection in prostates of Tobago men resulting in increased macrophage infiltration","volume":"76","author":"Henning","year":"2016","journal-title":"Prostate"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.3390\/v7041578","article-title":"Eradication of HIV-1 from the macrophage reservoir: An uncertain goal?","volume":"7","author":"Abbas","year":"2015","journal-title":"Viruses"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Toriyabe, K., Kitamura, A., Ikejiri, M., Hashizume, R., Nakamura, M., Teramoto, E., Takeuchi, H., Kondo, E., and Ikeda, T. (2024). Cytomegalovirus DNA Loads in Organs of Congenitally Infected Fetus. Viruses, 16.","DOI":"10.20944\/preprints202404.0010.v1"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kyrrestad, I., Larsen, A.K., S\u00e1nchez Romano, J., Sim\u00f3n-Santamar\u00eda, J., Li, R., and S\u00f8rensen, K.K. (2023). Infection of liver sinusoidal endothelial cells with Muromegalovirus muridbeta1 involves binding to neuropilin-1 and is dynamin-dependent. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1249894"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1099\/vir.0.80285-0","article-title":"Vascular endothelial and smooth muscle cells are unlikely to be major sites of latency of human cytomegalovirus in vivo","volume":"85","author":"Reeves","year":"2004","journal-title":"J. Gen. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1111\/j.1600-6143.2005.00912.x","article-title":"Renal ischemia\/reperfusion injury activates the enhancer domain of the human cytomegalovirus major immediate early promoter","volume":"5","author":"Kim","year":"2005","journal-title":"Am. J. Transplant."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev-virology-110615-042422","article-title":"Human Cytomegalovirus Latency: Approaching the Gordian Knot","volume":"3","author":"Goodrum","year":"2016","journal-title":"Annu. Rev. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00705-024-06114-3","article-title":"Polymorphisms in the genes encoding RLR and TLR3 and CMV DNAemia in subjects coinfected with human immunodeficiency virus and cytomegalovirus","volume":"169","author":"Kamerys","year":"2024","journal-title":"Arch. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00018-024-05369-y","article-title":"The battle between host antiviral innate immunity and immune evasion by cytomegalovirus","volume":"81","author":"Li","year":"2024","journal-title":"Cell Mol. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4670","DOI":"10.1038\/s41467-019-12641-4","article-title":"HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways","volume":"10","author":"Park","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7789","DOI":"10.1128\/JVI.01040-16","article-title":"cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection","volume":"90","author":"Lio","year":"2016","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.chom.2018.05.007","article-title":"Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate Immune Evasion","volume":"24","author":"Huang","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lim, E.Y., Jackson, S.E., and Wills, M.R. (2020). The CD4+ T Cell Response to Human Cytomegalovirus in Healthy and Immunocompromised People. Front. Cell Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00202"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28175","DOI":"10.1074\/jbc.M115.656660","article-title":"The VCP\/p97 and YOD1 Proteins Have Different Substrate-dependent Activities in Endoplasmic Reticulum-associated Degradation (ERAD)","volume":"290","author":"Sasset","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6757","DOI":"10.4049\/jimmunol.171.12.6757","article-title":"Human cytomegalovirus-encoded US2 differentially affects surface expression of MHC class I locus products and targets membrane-bound, but not soluble HLA-G1 for degradation","volume":"171","author":"Barel","year":"2003","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1073\/pnas.94.13.6904","article-title":"The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation","volume":"94","author":"Lehner","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/12478","article-title":"Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells","volume":"5","author":"Tomazin","year":"1999","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10929","DOI":"10.1128\/JVI.76.21.10929-10941.2002","article-title":"Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: A novel mechanism for evading major histocompatibility complex class II antigen presentation","volume":"76","author":"Hegde","year":"2002","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4870","DOI":"10.1182\/blood-2002-05-1504","article-title":"Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR alpha-chain","volume":"101","author":"Odeberg","year":"2003","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1006\/smim.2001.0291","article-title":"Cytomegalovirus and transcriptional down-regulation of major histocompatibility complex class II expression","volume":"13","author":"Miller","year":"2001","journal-title":"Semin. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1182\/blood-2008-03-143727","article-title":"MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response","volume":"112","author":"Yawata","year":"2008","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shirane, M., Yawata, N., Motooka, D., Shibata, K., Khor, S.S., Omae, Y., Kaburaki, T., Yanai, R., Mashimo, H., and Yamana, S. (2022). Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1008220"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S1074-7613(01)00095-4","article-title":"ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor","volume":"14","author":"Cosman","year":"2001","journal-title":"Immunity"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Fielding, C.A., Aicheler, R., Stanton, R.J., Wang, E.C., Han, S., Seirafian, S., Davies, J., McSharry, B.P., Weekes, M.P., and Antrobus, P.R. (2014). Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004058"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1128\/JVI.76.3.1285-1292.2002","article-title":"Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10","volume":"76","author":"Spencer","year":"2002","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/s41590-018-0082-6","article-title":"Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells","volume":"19","author":"Hammer","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Mart\u00edn Almaz\u00e1n, N., Sala, B.M., Sandalova, T., Sun, Y., Resink, T., Cichocki, F., S\u00f6derberg-Naucl\u00e9r, C., Miller, J.S., Achour, A., and Sarhan, D. (2023). Non-classical HLA-E restricted CMV 15-mer peptides are recognized by adaptive NK cells and induce memory responses. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1230718"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00005-023-00674-z","article-title":"Activating NKG2C Receptor: Functional Characteristics and Current Strategies in Clinical Applications","volume":"71","author":"Siemaszko","year":"2023","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Mocarski, E.S. (2024). Cytomegalovirus Biology Viewed Through a Cell Death Suppression Lens. Viruses, 16.","DOI":"10.3390\/v16121820"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7829","DOI":"10.1073\/pnas.141108798","article-title":"A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation","volume":"98","author":"Skaletskaya","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7988","DOI":"10.1073\/pnas.0401897101","article-title":"Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria","volume":"101","author":"Arnoult","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Mandal, P., Nagrani, L.N., Hernandez, L., McCormick, A.L., Dillon, C.P., Koehler, H.S., Roback, L., Alnemri, E.S., Green, D.R., and Mocarski, E.S. (2021). Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness. Viruses, 13.","DOI":"10.3390\/v13091707"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6232","DOI":"10.1128\/JVI.02710-07","article-title":"Cytomegalovirus proteins vMIA and m38.5 link mitochondrial morphogenesis to Bcl-2 family proteins","volume":"82","author":"Norris","year":"2008","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Krasovec, G., Renaud, C., Qu\u00e9innec, \u00c9., Sasakura, Y., and Chambon, J.P. (2024). Extrinsic apoptosis participates to tail regression during the metamorphosis of the chordate Ciona. Sci. Rep., 14.","DOI":"10.1038\/s41598-023-48411-y"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ebermann, L., Ruzsics, Z., Guzm\u00e1n, C.A., van Rooijen, N., Casalegno-Gardu\u00f1o, R., Koszinowski, U., and \u010ci\u010din-\u0160ain, L. (2012). Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1003062"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/82732","article-title":"Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule","volume":"1","author":"Holler","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.cell.2009.05.037","article-title":"Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation","volume":"137","author":"Cho","year":"2009","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100199","DOI":"10.1016\/j.mocell.2025.100199","article-title":"RIPK3 in necroptosis and cancer","volume":"48","author":"Morgan","year":"2025","journal-title":"Mol. Cells"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41418-023-01237-7","article-title":"MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis","volume":"31","author":"Liu","year":"2024","journal-title":"Cell Death Differ."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"18771","DOI":"10.1073\/pnas.2001887117","article-title":"Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor","volume":"117","author":"Nobre","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Wang, Y., Wei, W., Zhang, Y., Miao, J., Bao, X., and Lu, C. (2025). MLKL as an emerging machinery for modulating organelle dynamics: Regulatory mechanisms, pathophysiological significance, and targeted therapeutics. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1512968"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Adamson, C.S., and Nevels, M.M. (2020). Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function. Viruses, 12.","DOI":"10.3390\/v12010110"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.neo.2018.11.002","article-title":"Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells","volume":"21","author":"Knuth","year":"2019","journal-title":"Neoplasia"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Heusel, A.T., Rapp, S., Stamminger, T., and Scherer, M. (2024). IE1 of Human Cytomegalovirus Inhibits Necroptotic Cell Death via Direct and Indirect Modulation of the Necrosome Complex. Viruses, 16.","DOI":"10.3390\/v16020290"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.chom.2019.09.004","article-title":"DAI\/ZBP1\/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA","volume":"26","author":"Upton","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.chom.2016.05.011","article-title":"RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus","volume":"20","author":"Nogusa","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e46518","DOI":"10.15252\/embr.201846518","article-title":"Viral M45 and necroptosis-associated proteins form heteromeric amyloid assemblies","volume":"20","author":"Pham","year":"2019","journal-title":"EMBO Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1128\/JVI.05746-11","article-title":"The human cytomegalovirus protein TRS1 inhibits autophagy via its interaction with Beclin 1","volume":"86","author":"Chaumorcel","year":"2012","journal-title":"J. Virol."},{"key":"ref_77","first-page":"jcs254268","article-title":"CMV-encoded GPCR pUL33 activates CREB and facilitates its recruitment to the MIE locus for efficient viral reactivation","volume":"134","author":"Krishna","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1182\/blood-2016-10-748426","article-title":"The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality","volume":"129","author":"Hill","year":"2017","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1182\/blood.2019000956","article-title":"How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation","volume":"135","author":"Einsele","year":"2020","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1111\/j.1399-3062.2010.00504.x","article-title":"Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy","volume":"12","author":"George","year":"2010","journal-title":"Transpl. Infect. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1097\/JS9.0000000000001135","article-title":"Impact of varied immunosuppressive agents and post-transplant diabetes mellitus on prognosis among diverse transplant recipients (experimental studies)","volume":"110","author":"Liu","year":"2024","journal-title":"Int. J. Surg."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e01560-18","DOI":"10.1128\/mBio.01560-18","article-title":"Tumor Necrosis Factor Alpha Induces Reactivation of Human Cytomegalovirus Independently of Myeloid Cell Differentiation following Posttranscriptional Establishment of Latency","volume":"9","author":"Forte","year":"2018","journal-title":"mBio"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1093\/infdis\/jix192","article-title":"Identifying Cytomegalovirus Complications Using the Quantiferon-CMV Assay After Allogeneic Hematopoietic Stem Cell Transplantation","volume":"215","author":"Yong","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4814","DOI":"10.1128\/JVI.75.10.4814-4822.2001","article-title":"Allogeneic transplantation induces expression of cytomegalovirus immediate-early genes in vivo: A model for reactivation from latency","volume":"75","author":"Hummel","year":"2001","journal-title":"J. Virol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1099\/jgv.0.000407","article-title":"Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-\u03baB and AP-1 to the major immediate early promoter","volume":"97","author":"Liu","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"53","DOI":"10.5005\/jp-journals-10071-24079","article-title":"Immune Modulation and Cytomegalovirus Reactivation in Sepsis-induced Immunosuppression: A Pilot Study","volume":"26","author":"Lambe","year":"2022","journal-title":"Indian J. Crit. Care Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1007\/s00277-023-05121-9","article-title":"CMV infection is a risk factor for hemorrhagic cystitis after hematopoietic stem cell transplantation","volume":"102","author":"Zhang","year":"2023","journal-title":"Ann. Hematol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"102038","DOI":"10.1016\/j.trim.2024.102038","article-title":"Prior cytomegalovirus reactivation may lead to worse bacterial bloodstream infection outcomes in HSCT patients","volume":"84","author":"Li","year":"2024","journal-title":"Transpl. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s00277-023-05509-7","article-title":"The indirect effects of CMV reactivation on patients following allogeneic hematopoietic stem cell transplantation: An evidence mapping","volume":"103","author":"Wu","year":"2024","journal-title":"Ann. Hematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1182\/blood-2013-02-487074","article-title":"CMV reactivation after allogeneic HCT and relapse risk: Evidence for early protection in acute myeloid leukemia","volume":"122","author":"Green","year":"2013","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1182\/blood-2015-11-679639","article-title":"Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: A CIBMTR analysis","volume":"127","author":"Teira","year":"2016","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/MCP.0000000000001060","article-title":"The changing landscape of infections in the lung transplant recipient","volume":"30","author":"Lum","year":"2024","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_93","first-page":"377","article-title":"Cytomegalovirus infection in lung transplant recipients","volume":"11","author":"Almaghrabi","year":"2017","journal-title":"Expert. Rev. Respir. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1164\/rccm.200911-1786OC","article-title":"Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation","volume":"181","author":"Snyder","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"101689","DOI":"10.1016\/j.bpg.2020.101689","article-title":"Post liver transplant recurrent and de novo viral infections","volume":"46\u201347","author":"Jothimani","year":"2020","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.transproceed.2017.01.056","article-title":"Hepatic Artery Thrombosis After Liver Transplantation: Five-Year Experience at the State University of Campinas","volume":"49","author":"Boin","year":"2017","journal-title":"Transplant. Proc."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.cell.2023.11.044","article-title":"Cell death","volume":"187","author":"Newton","year":"2024","journal-title":"Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1161\/CIRCULATIONAHA.118.038379","article-title":"RIPK1 Expression Associates With Inflammation in Early Atherosclerosis in Humans and Can Be Therapeutically Silenced to Reduce NF-\u03baB Activation and Atherogenesis in Mice","volume":"143","author":"Karunakaran","year":"2021","journal-title":"Circulation"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C.M., Ligotti, M.E., Zareian, N., and Accardi, G. (2019). Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02247"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"20220557","DOI":"10.1515\/biol-2022-0557","article-title":"Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study","volume":"18","author":"Quan","year":"2023","journal-title":"Open Life Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1742-4933-5-6","article-title":"Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people","volume":"5","author":"Koch","year":"2008","journal-title":"Immun. Ageing"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Tu, W., and Rao, S. (2016). Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection. Front. Microbiol., 7.","DOI":"10.3389\/fmicb.2016.02111"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1084\/jem.20050882","article-title":"Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects","volume":"202","author":"Sylwester","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ebiom.2017.03.020","article-title":"Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link?","volume":"21","author":"Korolchuk","year":"2017","journal-title":"eBioMedicine"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12979-023-00352-w","article-title":"Aging and chronic inflammation: Highlights from a multidisciplinary workshop","volume":"20","author":"Saavedra","year":"2023","journal-title":"Immun. Ageing"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Wiech, M., Chroscicki, P., Swatler, J., Stepnik, D., De Biasi, S., Hampel, M., Brewinska-Olchowik, M., Maliszewska, A., Sklinda, K., and Durlik, M. (2022). Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.886431"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"100663","DOI":"10.1016\/j.xcrm.2022.100663","article-title":"The IL-1\u03b2, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19","volume":"3","author":"Willscher","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.abd.2022.09.004","article-title":"COVID-19 infection and vaccines: Potential triggers of Herpesviridae reactivation","volume":"98","author":"Ballano","year":"2023","journal-title":"An. Bras. Dermatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s41591-021-01283-z","article-title":"Post-acute COVID-19 syndrome","volume":"27","author":"Nalbandian","year":"2021","journal-title":"Nat. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s11357-020-00170-8","article-title":"Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging","volume":"42","author":"Jackson","year":"2020","journal-title":"Geroscience"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/10\/998\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T16:24:14Z","timestamp":1759422254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/10\/998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,2]]},"references-count":110,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["pathogens14100998"],"URL":"https:\/\/doi.org\/10.3390\/pathogens14100998","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,2]]}}}