Zika viral dynamics and shedding in rhesus and cynomolgus macaques.
Infection with Zika virus has been associated with serious neurological complications and fetal abnormalities. However, the dynamics of viral infection, replication and shedding are poorly understood. Here we show that both rhesus and cynomolgus macaques are highly susceptible to infection by lineages of Zika virus that are closely related to, or are currently circulating in, the Americas. After subcutaneous viral inoculation, viral RNA was detected in blood plasma as early as 1 d after infection. Viral RNA was also detected in saliva, urine, cerebrospinal fluid (CSF) and semen, but transiently in vaginal secretions. Although viral RNA during primary infection was cleared from blood plasma and urine within 10 d, viral RNA was detectable in saliva and seminal fluids until the end of the study, 3 weeks after the resolution of viremia in the blood. The control of primary Zika virus infection in the blood was correlated with rapid innate and adaptive immune responses. We also identified Zika RNA in tissues, including the brain and male and female reproductive tissues, during early and late stages of infection. Re-infection of six animals 45 d after primary infection with a heterologous strain resulted in complete protection, which suggests that primary Zika virus infection elicits protective immunity. Early invasion of Zika virus into the nervous system of healthy animals and the extent and duration of shedding in saliva and semen underscore possible concern for additional neurologic complications and nonarthropod-mediated transmission in humans.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Christa E
0000-0003-2761-2456
CE
Osuna
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
So-Yon
SY
Lim
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Claire
C
Deleage
National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
Bryan D
BD
Griffin
National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
Derek
D
Stein
National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
Lukas T
LT
Schroeder
National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
Robert Were
0000-0002-0421-110X
RW
Omange
Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Katharine
K
Best
National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
Ma
M
Luo
Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Peter T
PT
Hraber
Bioqual, Rockville, Maryland, USA.
Hanne
H
Andersen-Elyard
Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Erwing Fabian Cardozo
EF
Ojeda
Biosecurity Research Institute, Kansas State University, Manhattan, Kansas, USA.
Scott
S
Huang
Biosecurity Research Institute, Kansas State University, Manhattan, Kansas, USA.
Dana L
DL
Vanlandingham
Biosecurity Research Institute, Kansas State University, Manhattan, Kansas, USA.
Stephen
S
Higgs
Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
Alan S
AS
Perelson
Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Jacob D
JD
Estes
National Microbiology Laboratory, Winnipeg, Manitoba, Canada.
David
D
Safronetz
Bioqual, Rockville, Maryland, USA.
Mark G
MG
Lewis
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
James B
JB
Whitney
D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002555:Cerebrospinal Fluid / Q000821:virology; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D012367:RNA, Viral / Q000378:metabolism*; D012463:Saliva / Q000821:virology; D012661:Semen / Q000821:virology; D014556:Urine / Q000821:virology; D014766:Viremia / Q000276:immunology / Q000378:metabolism*; D017201:Virus Shedding; D000071244:Zika Virus / Q000235:genetics*; D000071243:Zika Virus Infection / Q000276:immunology / Q000378:metabolism*
D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012367:RNA, Viral
J Infect Dis. 2010 Dec 15;202(12):1804-12
21050124
N Engl J Med. 2016 Jun 2;374(22):2195-8
27074370
PLoS Pathog. 2007 Sep 14;3(9):1262-70
17941708
Lancet. 2016 Apr 2;387(10026):1482
27115821
PLoS Negl Trop Dis. 2016 Apr 12;10(4):e0004636
27070912
Lancet. 2016 Apr 9;387(10027):1531-9
26948433
PLoS One. 2012;7(12):e52215
23284941
Lancet. 2016 Jun 18;387(10037):2501
27287833
Trans R Soc Trop Med Hyg. 1952 Sep;46(5):509-20
12995440
Blood. 2010 Jun 3;115(22):4439-46
20339088
J Med Primatol. 1980;9(5):265-73
7441714
J Immunol Methods. 2011 Jan 5;363(2):166-76
20875419
Lancet. 1999 Nov 20;354(9192):1782-5
10577640
J Clin Virol. 2016 Oct;83:63-5
27598870
Cell Host Microbe. 2016 Aug 10;20(2):155-66
27443522
MMWR Morb Mortal Wkly Rep. 2016 Apr 15;65(14):372-4
27078057
PLoS Negl Trop Dis. 2012;6(11):e1887
23209847
Euro Surveill. 2014 Mar 06;19(9):null
24626205
Cytometry A. 2011 Feb;79(2):167-74
21265010
Immunology. 2005 Jun;115(2):206-14
15885126
J Immunol Methods. 2012 Dec 14;386(1-2):10-21
22955212
PLoS Curr. 2016 May 09;8:null
27280061
J Virol. 2015 Sep;89(17 ):8880-96
26085147
Emerg Infect Dis. 2016 Jul;22(7):1318-20
27070847
J R Soc Interface. 2016 Apr;13(117):null
27075003
Pathog Immun. 2016 Spring;1(1):68-106
27430032
N Engl J Med. 2016 Mar 10;374(10 ):951-8
26862926
Emerg Infect Dis. 2015 Jan;21(1):84-6
25530324
Emerg Infect Dis. 2015 Oct;21(10):1885-6
26401719
Emerg Infect Dis. 2011 May;17(5):880-2
21529401
Trans R Soc Trop Med Hyg. 1956 Sep;50(5):442-8
13380987
Nat Commun. 2016 Jun 28;7:12204
27352279
J Virol. 2006 Aug;80(15):7590-9
16840338
Am J Trop Med Hyg. 1976 Jan;25(1):146-50
3980
Lancet. 2014 Nov 1;384(9954):1571-2
25443481
MMWR Morb Mortal Wkly Rep. 2016 Jan 29;65(3):59-62
26820244
Emerg Infect Dis. 2016 Nov;22(11):1894-1899
27603576
AIDS. 2009 Jul 31;23(12):1453-60
19550289
J Immunol. 2002 Jan 1;168(1):29-43
11751943
Cell Host Microbe. 2016 Jun 8;19(6):771-4
27156023
J Clin Virol. 2015 Jul;68:53-5
26071336
Lancet. 2016 Apr 2;387(10026):1481
26946926
J Virol. 2013 Jan;87(1):701-5
23097444
Lancet. 2016 Jan 16;387(10015):228
26775125
Emerg Infect Dis. 2015 Feb;21(2):359-61
25625872
Lancet Infect Dis. 2016 Sep;16(9):1000-1
27427201
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3991-6
23431163
Arch Virol. 2015 Jun;160(6):1463-75
25860648
MMWR Morb Mortal Wkly Rep. 2016 May 13;65(18):475-8
27171533
Emerg Infect Dis. 2015 Dec;21(12):2274-6
26584464
Lancet Infect Dis. 2016 Jun;16(6):653-60
26897108
N Engl J Med. 2009 Jun 11;360(24):2536-43
19516034