140 |
Waters S., Agostino M., Lee S., Ariyanto I., Kresoje N., Leary S., Munyard K., Gaudieri S., Gaff J., Irish A., Keil A.D., Price P., Allcock R.J.N. |
57195514207;34771068500;56272877300;57193538110;55413004800;56906725500;6506851062;56245970200;57193534280;7004314741;57339623900;57201814264;7003764659; |
Sequencing directly from clinical specimens reveals genetic variations in HCMV-encoded chemokine receptor us28 that may influence antibody levels and interactions with human chemokines |
2021 |
Microbiology Spectrum |
9 |
2 |
e00020-21 |
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-85119150219&doi=10.1128%2fSpectrum.00020-21&partnerID=40&md5=d943d30d66f9a7de80628f87fcbb3810 |
Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; Curtin Institute for Computation, Curtin University, Bentley, WA, Australia; Department of Microbiology, PathWest Laboratory Medicine WA, Nedlands, WA, Australia; Virology and Cancer Pathobiology Research Center, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia; School of Human Sciences, University of Western Australia, Perth, WA, Australia; Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Nephrology, Fiona Stanley Hospital, Murdoch, WA, Australia; Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, WA, Australia |
Waters, S., Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; Agostino, M., Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia, Curtin Institute for Computation, Curtin University, Bentley, WA, Australia; Lee, S., Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia, Department of Microbiology, PathWest Laboratory Medicine WA, Nedlands, WA, Australia; Ariyanto, I., Virology and Cancer Pathobiology Research Center, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Kresoje, N., School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia; Leary, S., Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia; Munyard, K., Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; Gaudieri, S., Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia, School of Human Sciences, University of Western Australia, Perth, WA, Australia, Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, United States; Gaff, J., Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; Irish, A., Department of Nephrology, Fiona Stanley Hospital, Murdoch, WA, Australia; Keil, A.D., Department of Microbiology, PathWest Laboratory Medicine WA, Nedlands, WA, Australia; Price, P., Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; Allcock, R.J.N., School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia, Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, WA, Australia |
Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by;80% of the world’s population. Acute infections are asymptomatic in healthy individuals but generate diverse syndromes in neonates, solid organ transplant recipients, and HIV-infected individuals. The HCMV gene US28 encodes a homolog of a human chemokine receptor that is able to bind several chemokines and HIV gp120. Deep sequencing technologies were used to sequence US28 directly from 60 clinical samples from Indonesian HIV patients and Australian renal transplant recipients, healthy adults, and neonates. Molecular modeling approaches were used to predict whether nine nonsynonymous mutations in US28 may alter protein binding to a panel of six chemokines and two variants of HIV gp120. Ninety-two percent of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous mutation. Carriage of these variants differed between neonates and adults, Australian and Indonesian samples, and saliva samples and blood leukocytes. Two nonsynonymous mutations (N170D and R267K) were associated with increased levels of immediate early protein 1 (IE-1) and glycoprotein B (gB) HCMV-reactive antibodies, suggesting a higher viral burden. Seven of the nine mutations were predicted to alter binding of at least one ligand. Overall, HCMV variants are common in all populations and have the potential to affect US28 interactions with human chemokines and/or gp120 and alter responses to the virus. The findings relied on deep sequencing technologies applied directly to clinical samples, so the variants exist in vivo. IMPORTANCE Human cytomegalovirus (HCMV) is a common viral pathogen of solid organ transplant recipients, neonates, and HIV-infected individuals. HCMV encodes homologs of several host genes with the potential to influence viral persistence and/ or pathogenesis. Here, we present deep sequencing of an HCMV chemokine receptor homolog, US28, acquired directly from clinical specimens. Carriage of these variants differed between patient groups and was associated with different levels of circulating HCMV-reactive antibodies. These features are consistent with a role for US28 in HCMV persistence and pathogenesis. This was supported by in silico analyses of the variant sequences demonstrating altered ligand-binding profiles. The data delineate a novel approach to understanding the pathogenesis of HCMV and may impact the development of an effective vaccine. Copyright © 2021 Waters et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
Chemokine receptor; Deep sequencing; HIV patients; Human cytomegalovirus; Renal transplant recipients; US28 |
arginine; asparagine; aspartic acid; chemokine; chemokine receptor; chemokine receptor US28; glycoprotein B; glycoprotein gp 120; immediate early protein; immediate early protein 1; lysine; unclassified drug; virus antibody; chemokine; chemokine receptor; protein binding; US28 receptor, Cytomegalovirus; viral protein; virus antibody; adult; Article; Australian; blood; controlled study; genetic variation; graft recipient; human; Human cytomegalovirus; Human immunodeficiency virus infection; Indonesian; kidney transplantation; leukocyte; molecular model; mutation; newborn; nonhuman; protein protein interaction; saliva; virus load; amino acid sequence; blood; Cytomegalovirus; cytomegalovirus infection; genetic variation; genetics; high throughput sequencing; immunology; infant; isolation and |
American Society for Microbiology |
21650497 |
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34704798 |
Article |
Q1 |
2502 |
907 |
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