Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells
Identifieur interne : 000014 ( Pmc/Checkpoint ); précédent : 000013; suivant : 000015Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells
Auteurs : Bryan T. Mayer [États-Unis] ; Elizabeth M. Krantz [États-Unis] ; David Swan [États-Unis] ; James Ferrenberg [États-Unis] ; Karen Simmons [Canada] ; Stacy Selke [États-Unis] ; Meei-Li Huang [États-Unis] ; Corey Casper [États-Unis] ; Lawrence Corey [États-Unis] ; Anna Wald [États-Unis] ; Joshua T. Schiffer [États-Unis] ; Soren Gantt [États-Unis, Canada]Source :
- Journal of Virology [ 0022-538X ] ; 2017.
Abstract
Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication, as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia, and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection and validated them using clinical shedding data. Transient infections comprised 76 to 88% of oral CMV shedding events. For this high percentage of transient infections to occur, we identified two mathematical prerequisites: a very small number of initially infected oral cells (1 to 4) and low viral infectivity (<1.5 new cells infected/cell). These observations indicate that oral CMV infection in infants typically begins with a single virus that spreads inefficiently to neighboring cells. Thus, although the incidence of CMV infection is high during infancy, our data provide a mechanistic framework to explain why multiple CMV exposures are typically required before infection is successfully established. These findings imply that a sufficiently primed immune response could prevent CMV from establishing latent infection in humans and support the achievability of a prophylactic CMV vaccine.
Url:
DOI: 10.1128/JVI.00380-17
PubMed: 28381570
PubMed Central: 5446638
Affiliations:
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication, as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia, and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection and validated them using clinical shedding data. Transient infections comprised 76 to 88% of oral CMV shedding events. For this high percentage of transient infections to occur, we identified two mathematical prerequisites: a very small number of initially infected oral cells (1 to 4) and low viral infectivity (<1.5 new cells infected/cell). These observations indicate that oral CMV infection in infants typically begins with a single virus that spreads inefficiently to neighboring cells. Thus, although the incidence of CMV infection is high during infancy, our data provide a mechanistic framework to explain why multiple CMV exposures are typically required before infection is successfully established. These findings imply that a sufficiently primed immune response could prevent CMV from establishing latent infection in humans and support the achievability of a prophylactic CMV vaccine.</p>
<p><bold>IMPORTANCE</bold>
CMV infects the majority of the world's population and is a major cause of birth defects. Developing a vaccine to prevent CMV infection would be extremely valuable but would be facilitated by a better understanding of how natural human CMV infection is acquired. We studied CMV acquisition in infants and found that infections are usually brief and self-limited and are successfully established relatively rarely. Thus, although most people eventually acquire CMV infection, it usually requires numerous exposures. Our analyses indicate that this is because the virus is surprisingly inefficient, barely replicating well enough to spread to neighboring cells in the mouth. Greater knowledge of why CMV infection usually fails may provide insight into how to prevent it from succeeding.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Virol</journal-id>
<journal-id journal-id-type="hwp">jvi</journal-id>
<journal-id journal-id-type="pmc">jvi</journal-id>
<journal-id journal-id-type="publisher-id">JVI</journal-id>
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<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">28381570</article-id>
<article-id pub-id-type="pmc">5446638</article-id>
<article-id pub-id-type="publisher-id">00380-17</article-id>
<article-id pub-id-type="doi">10.1128/JVI.00380-17</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject>
</subj-group>
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<title-group><article-title>Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells</article-title>
<alt-title alt-title-type="running-head">Transient Cytomegalovirus Infection</alt-title>
<alt-title alt-title-type="short-authors">Mayer et al.</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Mayer</surname>
<given-names>Bryan T.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
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<contrib contrib-type="author"><name><surname>Krantz</surname>
<given-names>Elizabeth M.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>a</sup>
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<contrib contrib-type="author"><name><surname>Swan</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ferrenberg</surname>
<given-names>James</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Simmons</surname>
<given-names>Karen</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Selke</surname>
<given-names>Stacy</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Meei-Li</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Casper</surname>
<given-names>Corey</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Corey</surname>
<given-names>Lawrence</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wald</surname>
<given-names>Anna</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schiffer</surname>
<given-names>Joshua T.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Gantt</surname>
<given-names>Soren</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<aff id="aff1"><label>a</label>
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</aff>
<aff id="aff2"><label>b</label>
University of Washington, Seattle, Washington, USA</aff>
<aff id="aff3"><label>c</label>
University of British Columbia, BC Children's Hospital Research Institute, Vancouver, Canada</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Longnecker</surname>
<given-names>Richard M.</given-names>
</name>
<role>Editor</role>
<aff>Northwestern University</aff>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Soren Gantt, <email>sgantt@bcchr.ca</email>
.</corresp>
<fn fn-type="equal"><p>J.T.S. and S.G. contributed equally to this work.</p>
</fn>
<fn fn-type="other"><p><bold>Citation</bold>
Mayer BT, Krantz EM, Swan D, Ferrenberg J, Simmons K, Selke S, Huang M-L, Casper C, Corey L, Wald A, Schiffer JT, Gantt S. 2017. Transient oral human cytomegalovirus infections indicate inefficient viral spread from very few initially infected cells. J Virol 91:e00380-17. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00380-17">https://doi.org/10.1128/JVI.00380-17</ext-link>
.</p>
</fn>
</author-notes>
<pub-date pub-type="epreprint"><day>5</day>
<month>4</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="epub"><day>26</day>
<month>5</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="collection"><day>15</day>
<month>6</month>
<year>2017</year>
</pub-date>
<volume>91</volume>
<issue>12</issue>
<elocation-id>e00380-17</elocation-id>
<history><date date-type="received"><day>6</day>
<month>3</month>
<year>2017</year>
</date>
<date date-type="accepted"><day>27</day>
<month>3</month>
<year>2017</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2017 American Society for Microbiology.</copyright-statement>
<copyright-year>2017</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
<license license-type="asm" xlink:href="https://doi.org/10.1128/ASMCopyrightv1"><license-p><ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/ASMCopyrightv1">All Rights Reserved</ext-link>
.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="zjv012172655001.pdf"></self-uri>
<abstract><title>ABSTRACT</title>
<p>Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication, as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia, and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection and validated them using clinical shedding data. Transient infections comprised 76 to 88% of oral CMV shedding events. For this high percentage of transient infections to occur, we identified two mathematical prerequisites: a very small number of initially infected oral cells (1 to 4) and low viral infectivity (<1.5 new cells infected/cell). These observations indicate that oral CMV infection in infants typically begins with a single virus that spreads inefficiently to neighboring cells. Thus, although the incidence of CMV infection is high during infancy, our data provide a mechanistic framework to explain why multiple CMV exposures are typically required before infection is successfully established. These findings imply that a sufficiently primed immune response could prevent CMV from establishing latent infection in humans and support the achievability of a prophylactic CMV vaccine.</p>
<p><bold>IMPORTANCE</bold>
CMV infects the majority of the world's population and is a major cause of birth defects. Developing a vaccine to prevent CMV infection would be extremely valuable but would be facilitated by a better understanding of how natural human CMV infection is acquired. We studied CMV acquisition in infants and found that infections are usually brief and self-limited and are successfully established relatively rarely. Thus, although most people eventually acquire CMV infection, it usually requires numerous exposures. Our analyses indicate that this is because the virus is surprisingly inefficient, barely replicating well enough to spread to neighboring cells in the mouth. Greater knowledge of why CMV infection usually fails may provide insight into how to prevent it from succeeding.</p>
</abstract>
<kwd-group><title>KEYWORDS</title>
<kwd>Epstein-Barr virus</kwd>
<kwd>basic reproduction number</kwd>
<kwd>cytomegalovirus</kwd>
<kwd>founder population</kwd>
<kwd>herpes simplex virus</kwd>
<kwd>human herpesviruses</kwd>
<kwd>mathematical modeling</kwd>
<kwd>oral shedding</kwd>
<kwd>transient infection</kwd>
</kwd-group>
<funding-group><award-group id="award1"><funding-source id="gs1">BC Children's Hospital Foundation</funding-source>
<award-id rid="gs1">Salary Award</award-id>
<principal-award-recipient>Soren Gantt</principal-award-recipient>
</award-group>
<award-group id="award2"><funding-source id="gs2">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">https://doi.org/10.13039/100000002</named-content>
</funding-source>
<award-id rid="gs2">KL2-RR025015</award-id>
<principal-award-recipient>Soren Gantt</principal-award-recipient>
</award-group>
<award-group id="award3"><funding-source id="gs3">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">https://doi.org/10.13039/100000002</named-content>
</funding-source>
<award-id rid="gs3">P30-AI027757</award-id>
<principal-award-recipient>Soren Gantt</principal-award-recipient>
</award-group>
<award-group id="award4"><funding-source id="gs4">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">https://doi.org/10.13039/100000002</named-content>
</funding-source>
<award-id rid="gs4">P01-AI030731</award-id>
<principal-award-recipient>Stacy Selke</principal-award-recipient>
<principal-award-recipient>Meeili Huang</principal-award-recipient>
<principal-award-recipient>Corey Casper</principal-award-recipient>
<principal-award-recipient>Larry Corey</principal-award-recipient>
<principal-award-recipient>Anna Wald</principal-award-recipient>
<principal-award-recipient>Joshua Schiffer</principal-award-recipient>
</award-group>
<award-group id="award5"><funding-source id="gs5">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">https://doi.org/10.13039/100000002</named-content>
</funding-source>
<award-id rid="gs5">R01-CA138165</award-id>
<principal-award-recipient>Corey Casper</principal-award-recipient>
</award-group>
<award-group id="award6"><funding-source id="gs6">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">https://doi.org/10.13039/100000002</named-content>
</funding-source>
<award-id rid="gs6">P30-CA015704</award-id>
<principal-award-recipient>Corey Casper</principal-award-recipient>
<principal-award-recipient>Anna Wald</principal-award-recipient>
</award-group>
<award-group id="award7"><funding-source id="gs7">Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)
<named-content content-type="funder-id">https://doi.org/10.13039/501100000024</named-content>
</funding-source>
<award-id rid="gs7">MOP 136825</award-id>
<principal-award-recipient>Soren Gantt</principal-award-recipient>
</award-group>
</funding-group>
<counts><count count="5" count-type="supplementary-material"></count>
<fig-count count="4"></fig-count>
<table-count count="1"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="51"></ref-count>
<page-count count="13"></page-count>
<word-count count="9454"></word-count>
</counts>
<custom-meta-group><custom-meta><meta-name>cover-date</meta-name>
<meta-value>June 2017</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Canada</li>
<li>États-Unis</li>
</country>
<region><li>Washington (État)</li>
</region>
<settlement><li>Seattle</li>
</settlement>
<orgName><li>Université de Washington</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Washington (État)"><name sortKey="Mayer, Bryan T" sort="Mayer, Bryan T" uniqKey="Mayer B" first="Bryan T." last="Mayer">Bryan T. Mayer</name>
</region>
<name sortKey="Casper, Corey" sort="Casper, Corey" uniqKey="Casper C" first="Corey" last="Casper">Corey Casper</name>
<name sortKey="Casper, Corey" sort="Casper, Corey" uniqKey="Casper C" first="Corey" last="Casper">Corey Casper</name>
<name sortKey="Corey, Lawrence" sort="Corey, Lawrence" uniqKey="Corey L" first="Lawrence" last="Corey">Lawrence Corey</name>
<name sortKey="Corey, Lawrence" sort="Corey, Lawrence" uniqKey="Corey L" first="Lawrence" last="Corey">Lawrence Corey</name>
<name sortKey="Ferrenberg, James" sort="Ferrenberg, James" uniqKey="Ferrenberg J" first="James" last="Ferrenberg">James Ferrenberg</name>
<name sortKey="Gantt, Soren" sort="Gantt, Soren" uniqKey="Gantt S" first="Soren" last="Gantt">Soren Gantt</name>
<name sortKey="Huang, Meei Li" sort="Huang, Meei Li" uniqKey="Huang M" first="Meei-Li" last="Huang">Meei-Li Huang</name>
<name sortKey="Huang, Meei Li" sort="Huang, Meei Li" uniqKey="Huang M" first="Meei-Li" last="Huang">Meei-Li Huang</name>
<name sortKey="Krantz, Elizabeth M" sort="Krantz, Elizabeth M" uniqKey="Krantz E" first="Elizabeth M." last="Krantz">Elizabeth M. Krantz</name>
<name sortKey="Schiffer, Joshua T" sort="Schiffer, Joshua T" uniqKey="Schiffer J" first="Joshua T." last="Schiffer">Joshua T. Schiffer</name>
<name sortKey="Schiffer, Joshua T" sort="Schiffer, Joshua T" uniqKey="Schiffer J" first="Joshua T." last="Schiffer">Joshua T. Schiffer</name>
<name sortKey="Selke, Stacy" sort="Selke, Stacy" uniqKey="Selke S" first="Stacy" last="Selke">Stacy Selke</name>
<name sortKey="Swan, David" sort="Swan, David" uniqKey="Swan D" first="David" last="Swan">David Swan</name>
<name sortKey="Wald, Anna" sort="Wald, Anna" uniqKey="Wald A" first="Anna" last="Wald">Anna Wald</name>
<name sortKey="Wald, Anna" sort="Wald, Anna" uniqKey="Wald A" first="Anna" last="Wald">Anna Wald</name>
</country>
<country name="Canada"><noRegion><name sortKey="Simmons, Karen" sort="Simmons, Karen" uniqKey="Simmons K" first="Karen" last="Simmons">Karen Simmons</name>
</noRegion>
<name sortKey="Gantt, Soren" sort="Gantt, Soren" uniqKey="Gantt S" first="Soren" last="Gantt">Soren Gantt</name>
</country>
</tree>
</affiliations>
</record>
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