TY - JOUR
T1 - Viral opportunistic infections in Mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications
AU - Wu, Helen L.
AU - Weber, Whitney C.
AU - Shriver-Munsch, Christine
AU - Swanson, Tonya
AU - Northrup, Mina
AU - Price, Heidi
AU - Armantrout, Kimberly
AU - Robertson-LeVay, Mitchell
AU - Reed, Jason S.
AU - Bateman, Katherine B.
AU - Mahyari, Eisa
AU - Thomas, Archana
AU - Junell, Stephanie L.
AU - Hobbs, Theodore R.
AU - Martin, Lauren D.
AU - MacAllister, Rhonda
AU - Bimber, Benjamin N.
AU - Slifka, Mark K.
AU - Legasse, Alfred W.
AU - Moats, Cassandra
AU - Axthelm, Michael K.
AU - Smedley, Jeremy
AU - Lewis, Anne D.
AU - Colgin, Lois
AU - Meyers, Gabrielle
AU - Maziarz, Richard T.
AU - Burwitz, Benjamin J.
AU - Stanton, Jeffrey J.
AU - Sacha, Jonah B.
N1 - Funding Information:
We wish to acknowledge the animals that contributed to this study and express our respect and gratitude for their invaluable role in this research. We thank Leslie Kean for helpful discussions on CMV treatment, David Watkins for providing yellow fever vaccine 17D, Amgen, Inc, for providing Neupogen, Bristol‐Myers Squibb for providing belatacept, Roger Wiseman and David O'Connor for assistance with MCM MHC typing, and Margaret Terry, Wendy Price, and Erinn Stefanich for technical assistance with histology and immunohistochemistry. This work was supported by National Institutes of Health grants R21 AI112433 and R01 AI129703 awarded to JBS, AI079898 awarded to MKS, and P51 OD011092 awarded to the Oregon National Primate Research Center. The ONPRC Integrated Pathology Core provided support services for the research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities.
AB - Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities.
KW - Mauritian cynomolgus macaques
KW - cytomegalovirus
KW - hematopoietic stem cell transplantation
KW - lymphocryptovirus
KW - non-human primates
KW - opportunistic infections
KW - polyomavirus
KW - transplant complications
KW - yellow fever virus
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U2 - 10.1111/xen.12578
DO - 10.1111/xen.12578
M3 - Article
C2 - 31930750
AN - SCOPUS:85078606854
SN - 0908-665X
VL - 27
JO - Xenotransplantation
JF - Xenotransplantation
IS - 4
M1 - e12578
ER -