[Xenotranplantation and porcine endogenous retroviruses]. / Risque rétroviral endogène porcin (PERV) en xénotransplantation.

Xenotransplantation using pigs as the transplant source has the potential to resolve the severe shortage of human organ donors. Pig production is a very well controlled process and a high sanitary status for pig products is relatively easy to achieve allowing the production of pathogen free animals (SPF). However, whereas human genome express no more active endogenous retrovirus, pigs genomes posses several full length endogenous retroviral copies (PERV), which are still active. Evidences of PERV infection of human cell lines in vitro have been provided, highlighting the potential risk of cross-species infection associated with the use of porcine tissues in human. Further works have demonstrated that PERV risks are similar to the risk associated with other gammaretroviruses particularly for the integration of the proviral genome in the host's genome with a strong affinity for CpG islands and transcription start sites. Different technical solutions for the containment of this zoonotic risk are briefly presented.

Degradation of cyclins D in pseudorabies virus (PRV) infected proliferating cells.

The pseudorabies virus code for an ICP0 protein which is half the size of the HSV1 ICP0 protein. In this work, we made the assumption that some function might have been lost in the ICP0 from PRV. One function attributed to the ICP0 from HSV1 was the stabilization of cyclins D. We then looked at the stability of these cyclins during the lytic infection with the PRV. Our results show that cyclins D are not stabilized during infection with the PRV. These results are in accord with recent data from the literature.

Acute induction of cell death-related IFN stimulated genes (ISG) differentiates highly from moderately virulent CSFV strains.

Classical swine fever (CSF) severity is dependent on the virulence of the CSF virus (CSFV) strain. The earliest event detected following CSFV infection is a decrease in lymphocytes number. With some CSFV strains this leads to lymphopenia, the severity varying according to strain virulence. This lymphocyte depletion is attributed to an induction of apoptosis in non-infected bystander cells. We collected peripheral blood mononuclear cells (PBMC) before and during 3 days post-infection with either a highly or moderately virulent CSFV strain and subjected them to comparative microarray analysis to decipher the transcriptomic modulations induced in these cells in relation to strain virulence. The results revealed that the main difference between strains resided in the kinetics of host response to the infection: strong and immediate with the highly virulent strain, progressive and delayed with the moderately virulent one. Also although cell death/apoptosis-related IFN stimulated genes (ISG) were strongly up-regulated by both strains, significant differences in their regulation were apparent from the observed differences in onset and extent of lymphopenia induced by the two strains. Furthermore, the death receptors apoptotic pathways (TRAILDR4, FASL-FAS and TNFa-TNFR1) were also differently regulated. Our results suggest that CSFV strains might exacerbate the interferon alpha response, leading to bystander killing of lymphocytes and lymphopenia, the severity of which might be due to the host's loss of control of IFN production and downstream effectors regulation.

Porcine endogenous retrovirus integration sites in the human genome: features in common with those of murine leukemia virus.

Porcine endogenous retroviruses (PERV) are a major concern when porcine tissues and organs are used for xenotransplantation. PERV has been shown to infect human cells in vitro, highlighting a potential zoonotic risk. No pathology is associated with PERV in its natural host, but the pathogenic potential might differ in the case of cross-species transmission and can only be inferred from knowledge of related gammaretroviruses. We therefore investigated the integration features of the PERV DNA in the human genome in vitro in order to further characterize the risk associated with PERV transmission. In this study, we characterized 189 PERV integration site sequences from human HEK-293 cells. Data showed that PERV integration was strongly enhanced at transcriptional start sites and CpG islands and that the frequencies of integration events increased with the expression levels of the genes, except for the genes with the highest levels of expression, which were disfavored for integration. Finally, we extracted genomic sequences directly flanking the integration sites and found an original 8-base statistical palindromic consensus sequence [TG(int)GTACCAGC]. All these results show similarities between PERV and murine leukemia virus integration site selection, suggesting that gammaretroviruses have a common pattern of integration and that the mechanisms of target site selection within a retrovirus genus might be similar.