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Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

ABSTRACT: Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic "passenger leukocytes" harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation.

SUBMITTER: Allan JS

PROVIDER: S-EPMC2963433 | biostudies-literature | 1998 Jul

REPOSITORIES: biostudies-literature

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Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

Allan J S JS Broussard S R SR Michaels M G MG Starzl T E TE Leighton K L KL Whitehead E M EM Comuzzie A G AG Lanford R E RE Leland M M MM Switzer W M WM Heneine W W

AIDS research and human retroviruses 19980701 10

Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy v ...[more]

PMID: 9671210

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Project description:BACKGROUND & AIMS:A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles. METHODS:We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data. RESULTS:The mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of ?-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell-mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3. CONCLUSION:In an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.

Project description:BACKGROUND:Hearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection. METHODS:We conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir-velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation. RESULTS:A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders. CONCLUSIONS:In patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.).

Project description:ImportanceAllogeneic hematopoietic cell transplant (alloHCT) is known to increase the risk for keratinocyte carcinoma. The extent to which host characteristics, including pigmentary phenotype and UV radiation exposure, contribute is unknown.ObjectiveTo identify and validate independent risk factors for keratinocyte carcinoma after alloHCT, including those associated with the transplant and the host.Design, setting, and participantsThis retrospective cohort study analyzed a consecutive sample of alloHCT recipients from January 1, 2000, to December 31, 2014, at the Mayo Clinic, Rochester, Minnesota (n = 872) and University Hospitals Cleveland Medical Center, Cleveland, Ohio (n = 147). Participants from the Mayo Clinic were randomly allocated (2:1) into discovery (n = 581) and validation (n = 291) cohorts. Time to first keratinocyte carcinoma and information about transplant- and host-associated risk factors were extracted. A multivariate keratinocyte carcinoma risk model was created using a stepwise Cox proportional hazards regression model with P ≤ .05 for entry that incorporated all covariates that were individually statistically significant at α = 0.05 in the discovery cohort. The risk model was first internally validated using the Mayo Clinic validation cohort and then externally validated using the independent cohort of alloHCT recipients at University Hospitals Cleveland Medical Center. Data were analyzed from March 13, 2018, to June 12, 2019.ExposuresAllogeneic hematopoietic cell transplant.Main outcomes and measuresThe primary outcome was time to development of the first cutaneous keratinocyte carcinoma after alloHCT; secondary outcome, time to development of the first individual basal and/or squamous cell carcinoma after alloHCT.ResultsOf the 872 alloHCT recipients identified in the Mayo Clinic cohort (520 men [59.6%]; mean [SD] age, 48.3 [12.6] years), 95 (10.9%) developed keratinocyte carcinoma after alloHCT during 5349 person-years of follow-up. Of the 147 alloHCT recipients in the exernal validation cohort (86 men [58.5%]; mean [SD] age, 47.9 [17.5] years), 18 (12.2%) developed keratinocyte carcinoma after alloHCT in 880 person-years of follow up. Risk factors independently associated with keratinocyte carcinoma after alloHCT included age (hazard ratio [HR] per 10 years, 1.72; 95% CI, 1.21-2.42), chronic lymphocytic leukemia (HR, 2.47; 95% CI, 1.20-5.09), clinically photodamaged skin (HR, 3.47; 95% CI, 1.87-6.41), and history of cutaneous squamous cell carcinoma (HR, 2.60; 95% CI, 1.41-5.91). Harrell concordance statistics were 0.81 (95% CI, 0.72-0.90) and 0.86 (95% CI, 0.74-0.98) for internal and external validation of the keratinocyte carcinoma risk model, respectively.Conclusions and relevanceThis study found validated independent risk factors for keratinocyte carcinoma after alloHCT that are enriched with host- compared with transplant-associated risk factors. These findings highlight the importance of assessing host-associated risk factors for keratinocyte carcinoma in patients eligible for alloHCT. Future studies should examine whether keratinocyte carcinoma risk stratification before alloHCT may inform long-term surveillance strategies.

Dataset Information

Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

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Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

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