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Journal of Virology, May 2002, p. 4734-4740, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.4734-4740.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Activation of Cytomegalovirus in Pig-to-Primate Organ Xenotransplantation

Nicolas J. Mueller,1 Rolf N. Barth,2 Shin Yamamoto,2 Hiroshi Kitamura,2 Clive Patience,3 Kazuhiko Yamada,2 David K. C. Cooper,2 David H. Sachs,2 Amitinder Kaur,4 and Jay A. Fishman1*

Infectious Diseases Division, Massachusetts General Hospital and Harvard Medical School,1 Transplantation Biology Research Center, Massachusetts General Hospital,2 Immerge BioTherapeutics Inc., Charlestown,3 Division of Immunology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts4

Received 3 December 2001/ Accepted 19 February 2002

Xenotransplantation of porcine organs carries the risk of reactivation of latent virus in donor and recipient tissues as well as transmission of viruses between species. We have investigated the activation of baboon cytomegalovirus (BCMV) and porcine CMV (PCMV) in a pig-to-primate model of xenotransplantation. Tissues originating from a series of six swine-to-baboon composite thymokidney xenotransplants were investigated. Four immunosuppressed baboons died (survival range, 7 to 27 days) with the graft in situ. Increases in BCMV DNA copy numbers occurred in three (75%) of these baboons and was thought to be responsible for pneumonitis and the death of one animal. In two baboons, disseminated intravascular coagulation was successfully treated by graftectomy and discontinuation of immunosuppression. PCMV was upregulated in five of six xenografts (83%). PCMV infection was associated with ureteric necrosis in one xenograft. Although significantly increased in native tissues, low levels of BCMV and PCMV were also detected in tissues other than that of the native viral host species. The cross-species presence of CMV did not appear to cause clinical or histological signs of invasive disease. Thus, viral infections with clinical disease were restricted to tissues of the native species of each virus. Intensive immune suppression currently required for xenotransplantation results in a significant risk of reactivation of latent infections by BCMV and PCMV. It is not yet known whether viral DNA detected across species lines represents cellular microchimerism, ongoing viral infection, or uptake of free virus. The observation of graft injury by PCMV demonstrates that CMV will be an important pathogen in immunosuppressed xenograft recipients. Strategies must be developed to exclude CMV from porcine organ donors.

* Corresponding author. Mailing address: Transplantation Infectious Disease, Massachusetts General Hospital, 55 Fruit St., GRJ 504, Boston, MA 02114. Phone: (617) 726-5777. Fax: (617) 726-5411. E-mail: jfishman{at}partners.org.

Journal of Virology, May 2002, p. 4734-4740, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.4734-4740.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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