{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T21:11:19Z","timestamp":1780434679013,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T00:00:00Z","timestamp":1580688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["KL2-RR025015-01"],"award-info":[{"award-number":["KL2-RR025015-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007813","name":"University of Washington Center for AIDS Research","doi-asserted-by":"publisher","award":["P30-AI027757"],"award-info":[{"award-number":["P30-AI027757"]}],"id":[{"id":"10.13039\/100007813","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007813","name":"University of Washington Center for AIDS Research","doi-asserted-by":"publisher","award":["P01-AI 030731"],"award-info":[{"award-number":["P01-AI 030731"]}],"id":[{"id":"10.13039\/100007813","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007813","name":"University of Washington Center for AIDS Research","doi-asserted-by":"publisher","award":["R01-CA138165"],"award-info":[{"award-number":["R01-CA138165"]}],"id":[{"id":"10.13039\/100007813","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007813","name":"University of Washington Center for AIDS Research","doi-asserted-by":"publisher","award":["P30-CA015704"],"award-info":[{"award-number":["P30-CA015704"]}],"id":[{"id":"10.13039\/100007813","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) infections are common in early childhood. In a prospective Ugandan birth cohort study, most infants acquired HHV-6 (24\/31; 77%) and CMV (20\/30; 67%) during follow-up. To assess the transmission risk, we modeled a dose\u2013response relationship between infant HHV-6 and CMV infections and weekly oral viral shedding by mothers and all other (\u201csecondary\u201d) children in the home. Oral viral loads that were shed by mothers and secondary children were significantly associated with HHV-6 but not CMV transmission. While secondary children had higher and more frequent HHV-6 shedding than their mothers, they had a lower per-exposure transmission risk, suggesting that transmission to maternal contacts may be more efficient. HHV-6 transmission was relatively inefficient, occurring after &lt;25% of all weekly exposures. Although HHV-6 transmission often occurs following repeated, low dose exposures, we found a non-linear dose\u2013response relationship in which infection risk markedly increases when exposures reached a threshold of &gt; 5 log10 DNA copies\/mL. The lack of association between oral CMV shedding and transmission is consistent with breastfeeding being the dominant route of infant infection for that virus. These affirm saliva as the route of HHV-6 transmission and provide benchmarks for developing strategies to reduce the risk of infection and its related morbidity.<\/jats:p>","DOI":"10.3390\/v12020171","type":"journal-article","created":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T11:28:31Z","timestamp":1580729311000},"page":"171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Estimating the Risk of Human Herpesvirus 6 and Cytomegalovirus Transmission to Ugandan Infants from Viral Shedding in Saliva by Household Contacts"],"prefix":"10.3390","volume":"12","author":[{"given":"Bryan T.","family":"Mayer","sequence":"first","affiliation":[{"name":"Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Krantz","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wald","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"},{"name":"Department of Medicine, University of Washington, Seattle, WA 98195, USA"},{"name":"Department of Laboratory Medicine and Microbiology, University of Washington, Seattle, WA 98195, USA"},{"name":"Department of Epidemiology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Corey","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3609-661X","authenticated-orcid":false,"given":"Corey","family":"Casper","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Institute, University of Washington, Seattle, WA 98102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soren","family":"Gantt","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua T.","family":"Schiffer","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/cid\/ciu342","article-title":"Age-specific prevalence of Epstein-Barr virus infection among Minnesota children: Effects of race\/ethnicity and family environment","volume":"59","author":"Condon","year":"2014","journal-title":"Clin Infect Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/j.1348-0421.1997.tb01206.x","article-title":"Breast milk is not a significant source for early Epstein-Barr virus or human herpesvirus 6 infection in infants: A seroepidemiologic study in 2 endemic areas of human T-cell lymphotropic virus type I in Japan","volume":"41","author":"Kusuhara","year":"1997","journal-title":"Microbiol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1056\/NEJMoa042207","article-title":"A population-based study of primary human herpesvirus 6 infection","volume":"352","author":"Zerr","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/j.neuron.2018.11.043","article-title":"Alzheimer\u2019s Disease-Associated beta-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection","volume":"100","author":"Eimer","year":"2018","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neuron.2018.05.023","article-title":"Multiscale Analysis of Independent Alzheimer\u2019s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus","volume":"99","author":"Readhead","year":"2018","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S52","DOI":"10.1016\/S1386-6532(06)70012-9","article-title":"Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation","volume":"37","author":"Zerr","year":"2006","journal-title":"J. Clin. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1128\/CMR.00122-14","article-title":"Laboratory and clinical aspects of human herpesvirus 6 infections","volume":"28","author":"Agut","year":"2015","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1093\/infdis\/jiw076","article-title":"Prospective Characterization of the Risk Factors for Transmission and Symptoms of Primary Human Herpesvirus Infections Among Ugandan Infants","volume":"214","author":"Gantt","year":"2016","journal-title":"J. Infect. Dis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/infdis\/152.2.243","article-title":"Epidemiology and transmission of cytomegalovirus","volume":"152","author":"Pass","year":"1985","journal-title":"J. Infect. Dis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1172\/JCI45449","article-title":"Cytomegalovirus: Pathogen, paradigm, and puzzle","volume":"121","author":"Boeckh","year":"2011","journal-title":"J. Clin. Invest."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1097\/00002030-199404000-00007","article-title":"Cytomegalovirus colitis in HIV-1-infected patients: A prospective research in 55 patients","volume":"8","author":"Mentec","year":"1994","journal-title":"AIDS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/095646249300400603","article-title":"Cytomegalovirus retinitis: Diagnosis and treatment","volume":"4","author":"Maclean","year":"1993","journal-title":"Int J. STD AIDS"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1097\/INF.0000000000001975","article-title":"Congenital Cytomegalovirus and HIV Perinatal Transmission","volume":"37","author":"Adachi","year":"2018","journal-title":"Pediatr Infect. Dis. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1006\/clim.1998.4638","article-title":"Role of cytomegalovirus in the T cell changes seen in elderly individuals","volume":"90","author":"Looney","year":"1999","journal-title":"Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.4049\/jimmunol.170.4.2022","article-title":"Memory inflation: Continuous accumulation of antiviral CD8+ T cells over time","volume":"170","author":"Karrer","year":"2003","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.exger.2016.02.005","article-title":"Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: A systematic review","volume":"77","author":"Weltevrede","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Simanek, A.M., Dowd, J.B., Pawelec, G., Melzer, D., Dutta, A., and Aiello, A.E. (2011). Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016103"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2014.12.020","article-title":"Variation in the human immune system is largely driven by non-heritable influences","volume":"160","author":"Brodin","year":"2015","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1093\/cid\/ciy143","article-title":"Urinary Cytomegalovirus Shedding in the United States: The National Health and Nutrition Examination Surveys, 1999-2004","volume":"67","author":"Amin","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/S2352-4642(19)30024-0","article-title":"Transmission of CMV, HTLV-1, and HIV through breastmilk","volume":"3","author":"Prendergast","year":"2019","journal-title":"Lancet Child. Adolesc Health"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0140-6736(00)04043-5","article-title":"Epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding","volume":"357","author":"Hamprecht","year":"2001","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1056\/NEJM198005083021908","article-title":"Breast milk and the risk of cytomegalovirus infection","volume":"302","author":"Stagno","year":"1980","journal-title":"N. Engl J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Arvin, A., Campadelli-Fiume, G., Mocarski, E., Moore, P.S., Roizman, B., Whitley, R., and Yamanishi, K. (2007). HHV-6A, 6B, and 7: Persistence in the population, epidemiology and transmission. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis, Cambridge University Press.","DOI":"10.1017\/CBO9780511545313"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa035144","article-title":"Once-daily valacyclovir to reduce the risk of transmission of genital herpes","volume":"350","author":"Corey","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20140160","DOI":"10.1098\/rsif.2014.0160","article-title":"Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding","volume":"11","author":"Schiffer","year":"2014","journal-title":"J. R Soc. Interface"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1056\/NEJM200003303421303","article-title":"Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group","volume":"342","author":"Quinn","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"77ra29","DOI":"10.1126\/scitranslmed.3001888","article-title":"Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission","volume":"3","author":"Baeten","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Johnston, C., Orem, J., Okuku, F., Kalinaki, M., Saracino, M., Katongole-Mbidde, E., Sande, M., Ronald, A., McAdam, K., and Huang, M.L. (2009). Impact of HIV infection and Kaposi sarcoma on human herpesvirus-8 mucosal replication and dissemination in Uganda. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004222"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1128\/JCM.42.3.1142-1148.2004","article-title":"Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR","volume":"42","author":"Boeckh","year":"2004","journal-title":"J. Clin. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1128\/jcm.31.5.1262-1267.1993","article-title":"Human herpesvirus 6 DNA in peripheral blood cells and saliva from immunocompetent individuals","volume":"31","author":"Cone","year":"1993","journal-title":"J. Clin. Microbiol"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1086\/338044","article-title":"Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients","volume":"34","author":"Zerr","year":"2002","journal-title":"Clin. Infect. Dis"},{"key":"ref_33","unstructured":"R Core Team (2019). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_35","unstructured":"Therneau, T.M. (2015). A Package for Survival Analysis in S, Available online: http:\/\/cran.r-project.org\/package=survival."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hothorn, T., Hornik, K., van de Wiel, M.A., and Zeileis, A. (2008). Implementing a Class of Permutation Tests: The coin Package. J. Stat. Softw., 28.","DOI":"10.18637\/jss.v028.i08"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1198\/000313006X118430","article-title":"A Lego System for Conditional Inference","volume":"60","author":"Hothorn","year":"2006","journal-title":"Am. Stat."},{"key":"ref_38","unstructured":"Nocedal, J., and Wright, S.J. (2006). Numerical Optimization, Springer. [2nd ed.]."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1093\/comjnl\/7.4.308","article-title":"A Simplex Method for Function Minimization","volume":"7","author":"Nelder","year":"1965","journal-title":"Comput. J."},{"key":"ref_40","unstructured":"Carnell, R. (2019). lhs: Latin Hypercube Samples, Available online: https:\/\/github.com\/bertcarnell\/lhs."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Blischak, J., Carbonetto, P., and Stephens, M. (2019). Creating and sharing reproducible research code the workflowr way [version 1; peer review: 3 approved]. F1000Research, 8.","DOI":"10.12688\/f1000research.20843.1"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.jinf.2006.11.012","article-title":"Family saliva sharing behaviors and age of human herpesvirus-6B infection","volume":"54","author":"Rhoads","year":"2007","journal-title":"J. Infect."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/j.1442-200X.2009.02814.x","article-title":"Quantitative detection of HCMV-DNA in saliva from infants and breast milk on real-time polymerase chain reaction","volume":"51","author":"Murata","year":"2009","journal-title":"Pediatr. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1093\/cid\/cit727","article-title":"Compartmentalized cytomegalovirus replication and transmission in the setting of maternal HIV-1 infection","volume":"58","author":"Slyker","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1097\/INF.0000000000001877","article-title":"Nonprimary Maternal Cytomegalovirus Infection After Viral Shedding in Infants","volume":"37","author":"Boucoiran","year":"2018","journal-title":"Pediatr Infect. Dis. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1098\/rsif.2010.0491","article-title":"A dynamic dose-response model to account for exposure patterns in risk assessment: A case study in inhalation anthrax","volume":"8","author":"Mayer","year":"2011","journal-title":"J. R Soc. Interface"},{"key":"ref_47","first-page":"393","article-title":"A method to improve design reliability using optimal Latin hypercube sampling","volume":"12","author":"Stocki","year":"2005","journal-title":"Comput. Assist. Mech. Eng. Sci."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/2\/171\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:54:03Z","timestamp":1760172843000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/2\/171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,3]]},"references-count":47,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["v12020171"],"URL":"https:\/\/doi.org\/10.3390\/v12020171","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,3]]}}}