title: Reduced efficacy of ganciclovir against porcine and baboon cytomegalovirus in pig-to-baboon xenotransplantation.
abstract: In pig-to-baboon xenotransplantation, porcine cytomegalovirus (PCMV) causes viremia, consumptive coagulopathy, and tissue-invasive disease. Baboon cytomegalovirus (BCMV) is associated with invasive disease in xenograft recipients. The efficacy of prophylaxis with intravenous ganciclovir (GCV) was studied for prevention of PCMV and BCMV infections in pig-to baboon xenotransplantation. GCV prophylaxis did not alter the incidence of BCMV activation in recipients, but reduced the amount of virus in tissues (mean 8.38 x 10(2) vs. 3.24 x 10(5) copies/ micro g DNA without treatment) and prevented tissue-invasive infections. PCMV viral loads were unaltered by GCV prophylaxis (8.36 x 10(8) copies/ micro g DNA without prophylaxis vs. 1.20 x 10(9) copies/ micro g DNA with prophylaxis). In vitro, PCMV was relatively resistant to GCV [90% inhibitory concentration (IC90) of 10 micro m, IC50 = 3 micro m], acyclovir (100 micro m), and leflunomide (not achievable). Only cidofovir (IC90 1 micro m) and foscarnet (IC90 100 micro m) might have therapeutic efficacy for PCMV in vivo in achievable concentrations, although these agents often carry significant toxicity in transplant recipients. GCV has limited activity against BCMV and no therapeutic efficacy against PCMV at standard doses in vivo. GCV and other antiviral agents have limited activities against PCMV in vitro. Breeding of PCMV-free xenograft donors may be necessary to prevent PCMV infections in clinical trials.
authors.affiliation: Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Mueller
authors.forename: Kristen
authors.initials: K
authors.lastname: Sulling
authors.forename: Bernd
authors.initials: B
authors.lastname: Gollackner
authors.forename: Shin
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Christoph
authors.initials: C
authors.lastname: Knosalla
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wilkinson
authors.forename: Amitinder
authors.initials: A
authors.lastname: Kaur
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: Clive
authors.initials: C
authors.lastname: Patience
authors.forename: Jay A
authors.initials: JA
authors.lastname: Fishman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018958:CD55 Antigens / Q000235:genetics; D003587:Cytomegalovirus / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000517:prevention & control*; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000627:therapeutic use*; D016027:Heart Transplantation; D006801:Humans; D016030:Kidney Transplantation; D010215:Papio; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D013552:Swine; D013950:Thymus Gland / Q000637:transplantation; D014183:Transplantation, Heterologous; D019562:Viral Load
chemical_list: D018958:CD55 Antigens; D015774:Ganciclovir