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Zika viral dynamics and shedding in rhesus and cynomolgus macaques

Nature Medicine volume 22, pages 1448–1455 (2016)Cite this article

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A Corrigendum to this article was published on 07 February 2017

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Abstract

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.

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Figure 1: Blood plasma ZIKV RNA kinetics during primary infection.
Figure 2: Timing and magnitude of ZIKV shedding in CSF and mucosal fluids during primary infection.
Figure 3: Infection of rhesus macaques with a Puerto Rican ZIKV isolate.
Figure 4: Detection of ZIKV RNA in lymphoid, neurologic and reproductive tissues.
Figure 5: Protection against heterologous challenge with a Puerto Rican ZIKV isolate.

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  • 19 October 2016

    In the version of this article initially published online, Robert Were Omange's name was misspelled in the author list. The original version listed Robert Omage. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank B. Finneyfrock, Z. Pippin, A. Dodson and A. Cook for their expert animal husbandry and care, and J. Guedj for suggestions about the model simulations. CD38 antibodies were obtained from the NIH Nonhuman Primate Reagent Resource supported by HHSN272200900037C and OD010976. The data presented in this study are tabulated in the main paper and in the supplementary materials. This work was supported in part by federal funds from the National Cancer Institute (NIH Contract HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. A.S.P. acknowledges support from NIH grants AI028433 and OD0110995. D.S. acknowledges support from the Public Health Agency of Canada.

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Author notes

  1. Christa E Osuna, So-Yon Lim, David Safronetz and Mark G Lewis: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Christa E Osuna, So-Yon Lim & James B Whitney

  2. Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland

    Claire Deleage & Jacob D Estes

  3. National Microbiology Laboratory, Winnipeg, Manitoba, Canada

    Bryan D Griffin, Derek Stein, Lukas T Schroeder, Robert Omange, Ma Luo & David Safronetz

  4. Los Alamos National Laboratory, Los Alamos, New Mexico, USA

    Katharine Best, Peter T Hraber, Erwing Fabian Cardozo Ojeda & Alan S Perelson

  5. Bioqual, Rockville, Maryland, USA

    Hanne Andersen-Elyard & Mark G Lewis

  6. Biosecurity Research Institute, Kansas State University, Manhattan, Kansas, USA

    Scott Huang, Dana L Vanlandingham & Stephen Higgs

  7. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA

    James B Whitney

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Contributions

J.B.W. designed the studies. C.E.O., H.A.-E. and S.-Y.L. led the virologic assays. S.-Y.L. and C.E.O. led the immunologic assays. C.D. and J.D.E. led all tissue analysis. L.T.S., R.W.O. and M.L. conducted the cytokine assays. P.T.H, M.L., C.E.O. and S.-Y.L. led the cytokine and chemokine analysis. S.-Y.L. and P.T.H. led the peptide design analysis. B.D.G., D. Stein and D. Safronetz led the antibody assays. D.L.V., S. Huang, S. Higgs and D. Safronetz produced the ZIKV stocks K.B., E.F.C.O. and A.S.P. led the mathematical modeling. H.A.-E. and M.G.L. led the clinical care of the macaques. J.B.W. led the studies and wrote the paper with all co-authors.

Corresponding author

Correspondence to James B Whitney.

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The authors declare no competing financial interests.

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Osuna, C., Lim, SY., Deleage, C. et al. Zika viral dynamics and shedding in rhesus and cynomolgus macaques. Nat Med 22, 1448–1455 (2016). https://doi.org/10.1038/nm.4206

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