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Research Article

Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission

Kristy M. Bialas, Takayuki Tanaka, Dollnovan Tran, Valerie Varner, Eduardo Cisneros De La Rosa, Flavia Chiuppesi, Felix Wussow, Lisa Kattenhorn, Sheila Macri, Erika L. Kunz, Judy A. Estroff, Jennifer Kirchherr, Yujuan Yue, Qihua Fan, Michael Lauck, David H. O’Connor, Allison H. S. Hall, Alvarez Xavier, Don J. Diamond, Peter A. Barry, Amitinder Kaur, and Sallie R. Permar
PNAS November 3, 2015 112 (44) 13645-13650; first published October 19, 2015; https://doi.org/10.1073/pnas.1511526112
Kristy M. Bialas
aDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
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Takayuki Tanaka
bNew England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
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Dollnovan Tran
bNew England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
cTulane National Primate Research Center, Tulane University, Covington, LA 70433;
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Valerie Varner
bNew England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
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Eduardo Cisneros De La Rosa
aDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
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Flavia Chiuppesi
dDepartment of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
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Felix Wussow
dDepartment of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
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Lisa Kattenhorn
bNew England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
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Sheila Macri
bNew England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
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Erika L. Kunz
aDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
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Judy A. Estroff
eDepartment of Radiology, Boston’s Children Hospital, Boston, MA 02115;
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Jennifer Kirchherr
aDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
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Yujuan Yue
fCenter for Comparative Medicine, Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95616;
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Qihua Fan
aDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
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Michael Lauck
gDepartment of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53711;
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David H. O’Connor
gDepartment of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53711;
hWisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53711;
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Allison H. S. Hall
iDepartment of Pathology, Duke University, Durham, NC 27710
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Alvarez Xavier
cTulane National Primate Research Center, Tulane University, Covington, LA 70433;
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Don J. Diamond
dDepartment of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
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Peter A. Barry
fCenter for Comparative Medicine, Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95616;
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Amitinder Kaur
bNew England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
cTulane National Primate Research Center, Tulane University, Covington, LA 70433;
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  • For correspondence: Sallie.permar@duke.edu akaur@tulane.edu
Sallie R. Permar
aDuke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
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  • For correspondence: Sallie.permar@duke.edu akaur@tulane.edu
  1. Edited by Edward S. Mocarski, Emory University School of Medicine/Stanford University School of Medicine, Atlanta, GA, and accepted by the Editorial Board September 17, 2015 (received for review June 15, 2015)

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Significance

Congenital cytomegalovirus (CMV) is the leading infectious cause of childhood hearing loss and brain damage worldwide. Yet, despite its high prevalence and ranking as a top priority for vaccine development, the immune correlates of protection that could guide vaccine development remain undefined. Using a novel nonhuman primate model of congenital CMV transmission, we demonstrate a critical role for maternal CD4+ T cells in the induction of protective maternal immune responses that prevent fetal demise. In addition to establishing placental CMV transmission for the first time (to our knowledge) in nonhuman primates, this study reveals an association between delayed maternal virus-specific neutralizing antibody responses and severe fetal outcome, providing insight into the mechanism by which maternal CD4+ T cells impact congenital CMV disease.

Abstract

Elucidation of maternal immune correlates of protection against congenital cytomegalovirus (CMV) is necessary to inform future vaccine design. Here, we present a novel rhesus macaque model of placental rhesus CMV (rhCMV) transmission and use it to dissect determinants of protection against congenital transmission following primary maternal rhCMV infection. In this model, asymptomatic intrauterine infection was observed following i.v. rhCMV inoculation during the early second trimester in two of three rhCMV-seronegative pregnant females. In contrast, fetal loss or infant CMV-associated sequelae occurred in four rhCMV-seronegative pregnant macaques that were CD4+ T-cell depleted at the time of inoculation. Animals that received the CD4+ T-cell–depleting antibody also exhibited higher plasma and amniotic fluid viral loads, dampened virus-specific CD8+ T-cell responses, and delayed production of autologous neutralizing antibodies compared with immunocompetent monkeys. Thus, maternal CD4+ T-cell immunity during primary rhCMV infection is important for controlling maternal viremia and inducing protective immune responses that prevent severe CMV-associated fetal disease.

  • congenital cytomegalovirus
  • rhesus model
  • T-cell immunity
  • neutralizing antibody
  • rhesus CMV

Footnotes

  • ↵1A.K. and S.R.P. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: Sallie.permar{at}duke.edu or akaur{at}tulane.edu.
  • Author contributions: A.K. and S.R.P. designed research; J.K. organized and coordinated the study; K.M.B., T.T., D.T., V.V., E.C.D.L.R., F.C., F.W., L.K., S.M., E.L.K., J.A.E., and M.L. performed research; Y.Y., M.L., D.H.O., D.J.D., P.A.B., and A.K. contributed new reagents/analytic tools; K.M.B., F.C., L.K., S.M., E.L.K., J.A.E., J.K., Q.F., A.H.S.H., A.X., and A.K. analyzed data; and K.M.B., A.K., and S.R.P. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. E.S.M. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1511526112/-/DCSupplemental.

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Role of maternal CD4+ T cells in congenital rhCMV
Kristy M. Bialas, Takayuki Tanaka, Dollnovan Tran, Valerie Varner, Eduardo Cisneros De La Rosa, Flavia Chiuppesi, Felix Wussow, Lisa Kattenhorn, Sheila Macri, Erika L. Kunz, Judy A. Estroff, Jennifer Kirchherr, Yujuan Yue, Qihua Fan, Michael Lauck, David H. O’Connor, Allison H. S. Hall, Alvarez Xavier, Don J. Diamond, Peter A. Barry, Amitinder Kaur, Sallie R. Permar
Proceedings of the National Academy of Sciences Nov 2015, 112 (44) 13645-13650; DOI: 10.1073/pnas.1511526112

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Role of maternal CD4+ T cells in congenital rhCMV
Kristy M. Bialas, Takayuki Tanaka, Dollnovan Tran, Valerie Varner, Eduardo Cisneros De La Rosa, Flavia Chiuppesi, Felix Wussow, Lisa Kattenhorn, Sheila Macri, Erika L. Kunz, Judy A. Estroff, Jennifer Kirchherr, Yujuan Yue, Qihua Fan, Michael Lauck, David H. O’Connor, Allison H. S. Hall, Alvarez Xavier, Don J. Diamond, Peter A. Barry, Amitinder Kaur, Sallie R. Permar
Proceedings of the National Academy of Sciences Nov 2015, 112 (44) 13645-13650; DOI: 10.1073/pnas.1511526112
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