THE LANCET • Vol 352 • August 29, 1998 1 EARLY REPORTS Introduction Pigs are under consideration as a source of organs and tissues for xenotransplants. 1 Examples of porcine material already under study are fetal pig pancreatic islet cells and neural cells for insulin-dependent diabetes and refractory parkinsonism 2,3 and extracorporeal pig liver perfusion as a bridging strategy to treat liver failure. 4 The potential for infection of recipients with xenogeneic agents and the risk of transmission to the general population are major concerns, 5 and the risk of xenogeneic infection may be significantly increased by the immunosuppressive regimens required. The risks can be reduced or eliminated by using specific- pathogen-free animal colonies but this approach will not work for the porcine endogenous retrovirus (PERV) because the genome of these viruses is in the germline of every pig. PERV particles are released spontaneously by cell lines originating from pig kidney, lymph node, testis, and fallopian tube. 6–8 All PERVs originate from healthy tissues except ones from porcine lymphomas, and even there causation has not been established. 6,7 PERV have about 60% sequence homology to the gibbon ape leukaemia and murine leukaemia C-type retroviruses. 8–11 Retroviruses result in lifelong infection 12 and reports that PERV from cell lines and porcine lymphocytes can infect human cells in vitro 8,10 have prompted the US Food and Drug Administration to put porcine xenograft trials on hold until previously exposed patients are assessed for PERV infection and until prospective monitoring of xenograft recipients is established. We have studied 10 Swedish patients, transplanted with porcine fetal pancreatic islets between 1990 and 1993, for evidence of infection with PERV. These patients have been exposed to a large number of pig cells and xenograft survival has been prolonged. All these patients had a rise in antipig antibody titre within a month of transplantation. 13,14 Patients and Methods Patients 10 patients (mean age 40) with insulin-dependent diabetes of mean duration 30 years and end-stage diabetic nephropathy underwent transplantation with fetal porcine pancreatic islet- like cell clusters (ICC) procured from nontransgenic Swedish cross-bred pigs that had been extensively screened for conventional microbes. 2,15 Patients were given about 400 million to 2 billion cells (roughly 2000 per ICC). Maintenance immunosuppression was with cyclosporin, prednisolone, and azathioprine (prednisolone and azathioprine only in one) and at the time of the xenotransplantation, five patients were given adjunctive rabbit-antithymocyte globulin and the other five were given 15-deoxyspergualin. Summary Background The study of whether porcine xenografts can lead to porcine endogenous retrovirus (PERV) infection of recipients is critical for evaluating the safety of pig-to- man xenotransplantation. PERV is carried in the pig germline, and all recipients of porcine tissues or organs will be exposed to the virus. Methods We studied 10 diabetic patients who had received porcine fetal islets between 1990 and 1993, looking for evidence of PERV infection by using PCR serology, PCR, and reverse transcriptase assays. Prolonged xenograft survival (up to a year) was confirmed in five patients by porcine C-peptide excretion and detection of pig mitochondrial DNA (mtDNA) in serum. Findings Despite the evidence for extended exposure to pig cells and despite concomitant immunosuppressive therapy, we were unable to detect markers of PERV infection in any patient. Screening for two PERV sequences in peripheral blood lymphocytes collected 4–7 years after the xenotransplantation was negative. Markers of PERV expression, including viral RNA and reverse transcriptase, were undetectable in sera from both early (day 3 to day 180) and late (4–7 years) time points. Western blot analysis for antibodies was consistently negative. Interpretation These results suggested the absence of PERV infection in these patients. Also this study establishes a minimum standard for post-transplant surveillance of patients given porcine xenografts. Lancet 1998; 352: 695–99 See Commentary page 666 No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts Walid Heneine, Annika Tibell, William M Switzer, Paul Sandstrom, Guillermo Vazquez Rosales, Aprille Mathews, Olle Korsgren, Louisa E Chapman, Thomas M Folks, Carl G Groth HIV and Retrovirology Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA (W Heneine PHD, W M Switzer MPH, P Sandstrom PHD, G V Rosales MD, A Mathews BS, L E Chapman MD, T M Folks PHD) ; Department of Transplantation Surgery, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden (A Tibell MD, Prof C G Groth MD) ; and Department of Clinical Immunology, Academic Hospital, Uppsala University ( O Ko rs g re n PHD) Correspondence to: Dr Walid Heneine, HIV and Retroviriology Branch, Centers for Disease Control and Prevention, 1600 Clifton Road, NE, mail stop G-19, Atlanta, GA 30333, USA (e-mail: WMH2@cdc.gov)