Virus and host factors in pathogenesis

Abstract

Zoonoses pose a threat to mammalian species. Cross‐species transmission of viruses have given rise to fatal diseases because the host organism is not prepared to resist a new pathogen. Mammals have developed several strategies of defense against viruses, including an intracellular antiretroviral defense, a part of innate immunity. In addition to the conventional innate and acquired immune responses, complex organisms such as mice and primates have evolved an array of dominant, constitutively expressed genes that suppress or prevent retroviral infections. Several of these antiretroviral restriction mechanisms have recently been identified, with two particularly well described factors being members of the tripartite motif (TRIM) and APOBEC families. The TRIM5 class of inhibitors appears to target incoming retroviral capsids and the APOBEC class of cytidine deaminases hypermutates and destabilizes retroviral genomes. Lentiviruses such as HIV‐1 have developed countermeasures that allow them to replicate despite the human host factors. In the course of risk assessment for pig‐to‐human xenotransplantation the capacity of human cells to counteract infections of gamma‐type porcine endogenous retroviruses (PERV) should be analyzed. We raised the question as to whether PERV is affected by APOBEC3 proteins. Initial data indicate that human and porcine cytidine deaminases inhibit PERV replication, thereby possibly reducing the risk for infection of human cells by PERV as a consequence of pig‐to‐human xenotransplantation. The exact mechanism of the TRIM5 mediated restriction has not been clarified up to now. At current, we investigate how many TRIM5 genes are located in the pig genome. Furthermore, the properties of porcine TRIM5α isoform proteins will be tested and we will check the potential of the human TRIM5α to restrict PERVs in order to determine the risk of virus transmission.