Following the discovery that porcine endogenous retrovirus (PERV) can infect human cells, the potential risk of a zoonotic infection by PERV has been a major obstacle in the xenotransplantation field. The aim of this thesis is to gain a better understanding of PERV biology, so as to help assess and reduce the risk of PERV zoonosis. PERV subgroup A can enter human cells through two human PERV-A receptors (huPAR-1 and -2). To determine critical regions in the receptor for PERV-A infection, chimeric receptors between huPAR-2 and the non functional murine PAR (muPAR) have been analysed. A single amino acid difference (amino acid 109) was found responsible for the inability of muPAR to mediate PERV-A binding and infection. These results were then applied to the evaluation of PERV infection of non-human primates (NHP). NHP could represent an ideal animal model for assessing the risk of zoonosis following long-term exposure to porcine material. However, PERV does not infect NHP cells with the same efficiency as it does human cells. The data presented in this thesis suggests that in some NHP species the poor infectivity is due to mutation of the same critical amino acid (a.a.109) described for muPAR. However, African green monkey cells express two functional receptors and other mechanisms are likely to be responsible for the low susceptibility to PERV-A infection. Secondly, I evaluated the effect of a release inhibitor as a possible strategy to reduce PERV dissemination from pig cells. Human tetherin can inhibit retrovirus production from cells. I showed that overexpression of human and newly cloned porcine tetherin in pig cells can reduce the release of PERV. My data suggests that tetherin-expressing transgenic pigs could represent a safer donor in xenotransplantation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:564815 |
| Date | January 2010 |
| Creators | Mattiuzzo, G. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/19218/ |
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