Distribution of Cytomegalovirus Glycoprotein B Genotypes Among Renal and Haematopoietic Stem Cell Transplant Recipients in a Tertiary Hospital, Malaysia
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Abstract
Introduction: Cytomegalovirus (CMV) glycoprotein B (gB), encoded by gpUL55, is crucial for CMV's cellular entry and a potential pathogenicity marker. We investigated CMV gB genotype distribution in renal and haematopoietic stem cell transplant (HSCT) recipients, assessing correlations with disease. Materials and methods: 264 clinical samples from 110 renal and 154 HSCT recipients at a tertiary hospital in Kuala Lumpur, Malaysia were analysed. Quantitative PCR detected four CMV gB genotypes (gB1-4), and clinical data correlations were assessed. CMV serostatus of donors (D) and recipients (R) was determined pre-transplantation. Results: In renal transplant recipients, 48.2% exhibited single-genotype CMV, with gB2 (20.9%) and gB1 (17.3%) most prevalent. HSCT recipients showed 47.3% single-genotype CMV, primarily gB2 (20.7%) and gB1 (17.0%). Mixed-genotype infections were observed in 51.8% of renal transplant and 52.7% of HSCT recipients, particularly gB1-gB2 (65.8%). Mixed gB genotypes showed no significant CMV disease association in renal transplant recipients (p = 0.307) and HSCT recipients (p = 0.176). Virus load comparisons indicated significant differences in both groups, but renal transplant recipients with mixed infections had a higher median viral load. The majority of both recipient groups were D+/R+ (84.5% renal, 79.2% HSCT). Primary diagnoses among recipients varied, including glomerulonephritis, diabetes mellitus, hypertension, acute leukemias, lymphomas, and other conditions. Conclusion: This study reveals the diversity of CMV genotypes in renal and HSCT transplant recipients and their potential impact on disease correlation, providing insights into genotype prevalence, viral load association, and CMV disease risk.
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Styczyński J.. Who Is the Patient At Risk Of CMV Recurrence: A Review Of The Current Scientific Evidence With A Focus On Hematopoietic Cell Transplantation. Infect Dis Ther 2017;7(1):1-16. https://doi.org/10.1007/s40121-017-0180-z
Wille PT, Wisner TW, Ryckman B, Johnson DC. Human Cytomegalovirus (HCMV) Glycoprotein gB Promotes Virus Entry In Trans Acting as the Viral Fusion Protein Rather than as a Receptor-Binding Protein. Hutt-Fletcher L, Nemerow G, editors. mBio. 2013 Jun 4;4(3).
Sarkar A, Das D, Ansari S, Chatterjee RP, Mishra L, Basu B, et al. Genotypes of glycoprotein B gene among the Indian symptomatic neonates with congenital CMV infection. BMC Pediatrics. 2019 Aug 22;19(1). https://doi.org/10.1186/s12887-019-1666-5
Girmenia C., Lazzarotto T., Bonifazi F., Patriarca F., Irrera G., Ciceri F.et al.. Assessment and Prevention Of Cytomegalovirus Infection In Allogeneic Hematopoietic Stem Cell Transplant And In Solid Organ Transplant: A Multidisciplinary Consensus Conference By The Italian Gitmo, Sito, And Amcli Societies. Clin Transplant 2019;33(10). https://doi.org/10.1111/ctr.13666
Jenks J., Nelson C., Roark H., Goodwin M., Pass R., Bernstein D.et al.. Antibody Binding To Native Cytomegalovirus Glycoprotein B Predicts Efficacy Of the Gb/mf59 Vaccine In Humans. Sci. Transl. Med. 2020;12(568). https://doi.org/10.1126/scitranslmed.abb3611
Shah A., Chen J., Fridell J.. Incidence and Outcomes Of Cytomegalovirus In Pancreas Transplantation With Steroid-free Immunosuppression. Clin Transplant 2015;29(12):1221-1229. https://doi.org/10.1111/ctr.12655
Jung S., Michel M., Stamminger T., Michel D.. Fast Breakthrough Of Resistant Cytomegalovirus During Secondary Letermovir Prophylaxis In a Hematopoietic Stem Cell Transplant Recipient. BMC Infect Dis 2019;19(1). https://doi.org/10.1186/s12879-019-4016-1
Kobashigawa J., Ross H., Bara C., Delgado J., Dengler T., Lehmkuhl H.et al.. Everolimus Is Associated With a Reduced Incidence Of Cytomegalovirus Infection Followingde Novocardiac Transplantation. Transpl Infect Dis 2012;15(2):150-162. https://doi.org/10.1111/tid.12007
Hu H., Peng Q., Chen K.. Clinical Features, Treatment Courses, and Distribution Of Cytomegalovirus Genotypes Among Thrombocytopenia Patients Aged Younger Than 12 Months. Am J Perinatol 2020;38(13):1403-1411. https://doi.org/10.1055/s-0040-1713001
Choo H., Cher W., Kwan Y., Fong W.. Risk Factors For Cytomegalovirus Disease In Systemic Lupus Erythematosus (Sle): a Systematic Review. Adv Rheumatol 2019;59(1). https://doi.org/10.1186/s42358-019-0055-y
Felipe C., Ferreira A., Paula M., Viana L., Cristelli M., Medina-Pestana J.et al.. Incidence and Risk Factors Associated With Cytomegalovirus Infection After The Treatment Of Acute Rejection During The First Year In Kidney Transplant Recipients Receiving Preemptive Therapy. Transpl Infect Dis 2019;21(6). https://doi.org/10.1111/tid.13106
Meeralam Y., Qurashi B., Masoudi A., Alhejaili T., Khayat M., Aljoaid A.et al.. Cytomegalovirus Colitis In a Patient With Ulcerative Colitis On Vedolizumab Monotherapy. Cureus 2023. https://doi.org/10.7759/cureus.35473
Pardieck I., Duikeren S., Veerkamp D., Brasem D., Redeker A., Bergen J.et al.. Dominant Antiviral Cd8+ T Cell Responses Empower Prophylactic Antibody-eliciting Vaccines Against Cytomegalovirus. Front. Immunol. 2022;13. https://doi.org/10.3389/fimmu.2022.680559
Manuel O, Åsberg A, Pang X, Rollag H, Emery Vincent C, Preiksaitis J, et al. Impact of Genetic Polymorphisms in Cytomegalovirus Glycoprotein B on Outcomes in Solid-Organ Transplant Recipients with Cytomegalovirus Disease. Clinical Infectious Diseases. 2009 Oct 15;49(8):1160–6.
Hashim A., Altayb H., Saeed S., Abdalla W., Omer A.. Molecular Detection and Glycoprotein B (Ul55) Genotyping Of Cytomegalovirus Among Sudanese Renal Transplant Recipients. BioMed Research International 2022;2022:1-9. https://doi.org/10.1155/2022/5403694
Dieamant D., Bonon S., Aranha F., Duarte G., Fernandes V., Souza C.et al.. Cytomegalovirus (Cmv) Gb3 Genotype Is Associated With Acute Gvhd and CMV Disease In Allogeneic Hematopoietic Stem Cell Transplant Recipients (Hsct). Blood 2011;118(21):1958-1958. https://doi.org/10.1182/blood.v118.21.1958.1958
Hashim A., Altayb H., Saeed S., Abdalla W., Omer A.. Molecular Detection and Glycoprotein B (Ul55) Genotyping Of Cytomegalovirus Among Sudanese Renal Transplant Recipients. BioMed Research International 2022;2022:1-9. https://doi.org/10.1155/2022/5403694
Khalafkhany D., Makhdoomi K., Afshari A., Motazakker M.. Prevalence and Genotype Distribution Of Cytomegalovirus Ul55 Sequence In Renal Transplant Recipients In North West Of Iran. J. Med. Virol. 2016;88(9):1622-1627. https://doi.org/10.1002/jmv.24509
Wu X., Wang Y., Xu Y., Wu D., Sun A., Zhu Z.et al.. Cytomegalovirus Glycoprotein B Genotype In Hematopoietic Stem Cell Transplant Patients From China. Biology of Blood and Marrow Transplantation 2010;16(5):647-652. https://doi.org/10.1016/j.bbmt.2009.12.001
Wang H., Valencia S., Pfeifer S., Jensen J., Kowalik T., Permar S.. Common Polymorphisms In the Glycoproteins Of Human Cytomegalovirus And Associated Strain-specific Immunity. Viruses 2021;13(6):1106. https://doi.org/10.3390/v13061106
Cudini J., Roy S., Houldcroft C., Bryant J., Depledge D., Tutill H.et al.. Human Cytomegalovirus Haplotype Reconstruction Reveals High Diversity Due To Superinfection and Evidence Of Within-host Recombination. Proc. Natl. Acad. Sci. U.S.A. 2019;116(12):5693-5698. https://doi.org/10.1073/pnas.1818130116
Pati S., Pinninti S., Novak Z., Chowdhury N., Patro R., Fowler K.et al.. Genotypic Diversity and Mixed Infection In Newborn Disease And Hearing Loss In Congenital Cytomegalovirus Infection. The Pediatric Infectious Disease Journal 2013;32(10):1050-1054. https://doi.org/10.1097/inf.0b013e31829bb0b9
Wang Z., Sheng Q., Fan X., Sun X.. Polymorphisms Of the Cytomegalovirus Glycoprotein B Genotype In Patients With Posner-schlossman Syndrome. Br J Ophthalmol 2021;106(9):1240-1244. https://doi.org/10.1136/bjophthalmol-2020-318284
Hu H., Peng Q., Chen K.. Clinical Features, Treatment Courses, and Distribution Of Cytomegalovirus Genotypes Among Thrombocytopenia Patients Aged Younger Than 12 Months. Am J Perinatol 2020;38(13):1403-1411. https://doi.org/10.1055/s-0040-1713001
Paradowska E., Studzińska M., Suski P., Kasztelewicz B., Wiśniewska-Ligier M., Zawilińska B.et al.. Human Cytomegalovirus Ul55, Ul144, and Us28 Genotype Distribution In Infants Infected Congenitally Or Postnatally. J. Med. Virol. 2015;87(10):1737-1748. https://doi.org/10.1002/jmv.24222
Cella E., Rittà M., Ciccozzi M., Cavallo R., Perno C., Costa C.. Cytomegalovirus Glycoprotein B Genotype Distribution In Italian Transplant Patients. Intervirology 2017;60(4):165-170. https://doi.org/10.1159/000486593
Berg C., Rosenkilde M., Benfield T., Nielsen L., Sundelin T., Lüttichau H.. The Frequency Of Cytomegalovirus Non-elr Ul146 Genotypes In Neonates With Congenital CMV Disease Is Comparable To Strains In the Background Population. BMC Infect Dis 2021;21(1). https://doi.org/10.1186/s12879-021-06076-w
White J., Patel E., Abraham A., Grabowski M., Arav-Boger R., Avery R.et al.. Prevalence, Magnitude, and Genotype Distribution Of Urinary Cytomegalovirus (Cmv) Shedding Among Cmv-seropositive Children And Adolescents In The United States. Open Forum Infectious Diseases 2019;6(7). https://doi.org/10.1093/ofid/ofz272
Nijman J., Mandemaker F., Verboon-Maciolek M., Aitken S., Loon A., Vries L.et al.. Genotype Distribution, Viral Load and Clinical Characteristics Of Infants With Postnatal Or Congenital Cytomegalovirus Infection. PLoS ONE 2014;9(9):e108018. https://doi.org/10.1371/journal.pone.0108018
Manuel O., Åsberg A., Pang X., Rollag H., Emery V., Preiksaitis J.et al.. Impact Of Genetic Polymorphisms In Cytomegalovirus Glycoprotein B On Outcomes In Solid-organ Transplant Recipients With Cytomegalovirus Disease. CLIN INFECT DIS 2009;49(8):1160-1166. https://doi.org/10.1086/605633
Hashim A., Altayb H., Saeed S., Abdalla W., Omer A.. Molecular Detection and Glycoprotein B (Ul55) Genotyping Of Cytomegalovirus Among Sudanese Renal Transplant Recipients. BioMed Research International 2022;2022:1-9. https://doi.org/10.1155/2022/5403694
Selvey L., Lim W., Boan P., Swaminathan R., Slimings C., Harrison A.et al.. Cytomegalovirus Viraemia and Mortality In Renal Transplant Recipients In The Era Of Antiviral Prophylaxis. Lessons From The Western Australian Experience. BMC Infect Dis 2017;17(1). https://doi.org/10.1186/s12879-017-2599-y
Smith J., Corey L., Bittner R., Finn L., Healey P., Davis C.et al.. Subclinical Viremia Increases Risk For Chronic Allograft Injury In Pediatric Renal Transplantation. Journal of the American Society of Nephrology 2010;21(9):1579-1586. https://doi.org/10.1681/asn.2009111188
El Helou G, Razonable R. Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review. Infection and Drug Resistance. 2019 Jun;Volume 12:1481–91. https://doi.org/10.2147/idr.s180908
Hiwarkar P., Gaspar H., Gilmour K., Jagani M., Chiesa R., Bennett-Rees N.et al.. Impact Of Viral Reactivations In the Era Of Pre-emptive Antiviral Drug Therapy Following Allogeneic Haematopoietic Sct In Paediatric Recipients. Bone Marrow Transplant 2012;48(6):803-808. https://doi.org/10.1038/bmt.2012.221
Vallejo M., Muñiz P., Kwon M., Solán L., Bailén R., Carbonell D.et al.. Risk Prediction Of CMV Reactivation After Allogeneic Stem Cell Transplantation Using Five Non-hla Immunogenetic Polymorphisms. Ann Hematol 2022;101(7):1567-1576. https://doi.org/10.1007/s00277-022-04841-8
Manuel O., Åsberg A., Pang X., Rollag H., Emery V., Preiksaitis J.et al.. Impact Of Genetic Polymorphisms In Cytomegalovirus Glycoprotein B On Outcomes In Solid-organ Transplant Recipients With Cytomegalovirus Disease. CLIN INFECT DIS 2009;49(8):1160-1166. https://doi.org/10.1086/605633
Huang C., Cheng Y., Hwang Y., Kang E., Hsiao C.. Cytomegalovirus Glycoprotein B Genotype In Patients With Anterior Segment Infection. IJMS 2023;24(7):6304. https://doi.org/10.3390/ijms24076304
Zou J.. Clinical Manifestations and Outcomes Of Renal Transplantation Patients With Pneumocystis Jirovecii Pneumonia And Cytomegalovirus Co-infection. Front. Med. 2022;9. https://doi.org/10.3389/fmed.2022.860644
Teschner D., Knop J., Piehl C., Junker S., Witzke O.. Cytomegalovirus Infection and Rehospitalization Rates After Allogeneic Hematopoietic Stem Cell And Solid Organ Transplantation: A Retrospective Cohort Study Using German Claims Data. Infection 2022;50(6):1543-1555. https://doi.org/10.1007/s15010-022-01847-2
Chen P., Du Z., Qiu S., Wang H., Zhang J., Liu D.. Current Research Status Of Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation: a Bibliometric Analysis. Ann Palliat Med 2021;10(9):9614-9626. https://doi.org/10.21037/apm-21-2301
Yu X., Shang Q., Liu X., He M., Pei X., Mo X.et al.. Donor Nkg2c Homozygosity Contributes To CMV Clearance After Haploidentical Transplantation. Jci Insight 2022;7(3). https://doi.org/10.1172/jci.insight.149120
Ljungman P., Hakki M., Boeckh M.. Cytomegalovirus In Hematopoietic Stem Cell Transplant Recipients. Hematology/Oncology Clinics of North America 2011;25(1):151-169. https://doi.org/10.1016/j.hoc.2010.11.011
Huang C., Cheng Y., Hwang Y., Kang E., Hsiao C.. Cytomegalovirus Glycoprotein B Genotype In Patients With Anterior Segment Infection. IJMS 2023;24(7):6304. https://doi.org/10.3390/ijms24076304
Liu S., Bos N., Verschuuren E., Baarle D., Westra J.. Biological Characteristics Of Hla-g and Its Role In Solid Organ Transplantation. Front. Immunol. 2022;13. https://doi.org/10.3389/fimmu.2022.902093
Mostafa M., Fathy A., Elwasify M., Abdelsalam M.. Analysis Of Selected Polymorphisms In Foxp3 Gene In a Cohort Of Egyptian Patients With Schizophrenia. J Genet Eng Biotechnol 2022;20(1). https://doi.org/10.1186/s43141-022-00371-y
Barani R., Mani M., Sarangan G., Soundararajan P., Palani G., Srikanth P.. CMV Genotyping Using Different Samples In Post Renal Transplant Recipients With Cmv Disease. Can J Biotech 2017;1(Special Issue):93-93. https://doi.org/10.24870/cjb.2017-a80
Vogel JU, Otte J, Koch F, H. Gümbel, Hans Wilhelm Doerr, Jindrich Cinatl. Role of human cytomegalovirus genotype polymorphisms in AIDS patients with cytomegalovirus retinitis. 2012 Jun 6;202(1):37–47. https://doi.org/10.1007/s00430-012-0244-3
Aldo Albuquerque Cunha, Vitor Coronel Aquino, Viviane Casagrande Mariguela, Maurício Lacerda Nogueira, Luiz. Evaluation of glycoprotein B genotypes and load of CMV infecting blood leukocytes on prognosis of AIDS patients. 2011 Apr 1;53(2):82–8. https://doi.org/10.1007/s00430-012-0244-3
Jenks, Jennifer A, et al. Antibody Binding to Native Cytomegalovirus Glycoprotein B Predicts Efficacy of the GB/MF59 Vaccine in Humans. Vol. 12, no. 568, 4 Nov. 2020, https://doi.org/10.1126/scitranslmed.abb3611. Accessed 6 Aug. 2023.