Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission.
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.
Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
Kristy M
KM
Bialas
New England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
Takayuki
T
Tanaka
New England Primate Research Center, Harvard Medical School, Southborough, MA 01772; Tulane National Primate Research Center, Tulane University, Covington, LA 70433;
Dollnovan
D
Tran
New England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
Valerie
V
Varner
Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
Eduardo
E
Cisneros De La Rosa
Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
Flavia
F
Chiuppesi
Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
Felix
F
Wussow
New England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
Lisa
L
Kattenhorn
New England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
Sheila
S
Macri
Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
Erika L
EL
Kunz
Department of Radiology, Boston's Children Hospital, Boston, MA 02115;
Judy A
JA
Estroff
Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
Jennifer
J
Kirchherr
Center for Comparative Medicine, Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95616;
Yujuan
Y
Yue
Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710;
Qihua
Q
Fan
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53711;
Michael
M
Lauck
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53711; Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53711;
David H
DH
O'Connor
Department of Pathology, Duke University, Durham, NC 27710.
Allison H S
AH
Hall
Tulane National Primate Research Center, Tulane University, Covington, LA 70433;
Alvarez
A
Xavier
Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
Don J
DJ
Diamond
Center for Comparative Medicine, Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95616;
Peter A
PA
Barry
New England Primate Research Center, Harvard Medical School, Southborough, MA 01772; Tulane National Primate Research Center, Tulane University, Covington, LA 70433; Sallie.permar@duke.edu akaur@tulane.edu.
Amitinder
A
Kaur
Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710; Sallie.permar@duke.edu akaur@tulane.edu.
Sallie R
SR
Permar
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000151:congenital / Q000517:prevention & control* / Q000635:transmission; D004195:Disease Models, Animal; D005260:Female; D018445:Infectious Disease Transmission, Vertical; D008253:Macaca mulatta; D008431:Maternal-Fetal Exchange; D011247:Pregnancy
D000914:Antibodies, Viral
T-cell immunity; congenital cytomegalovirus; neutralizing antibody; rhesus CMV; rhesus model