Retroviral restriction factors and infectious risk in xenotransplantation

Abstract

The clinical application of xenotransplantation poses immunologic, ethical, and microbiologic challenges. Significant progress has been made in the investigation of each of these areas. Among concerns regarding infectious risks for human xenograft recipients is the identification in swine of infectious agents including porcine endogenous retroviruses (PERV) that are capable of replication in some human cell lines. PERV replication has, however, been difficult to demonstrate in primate-derived cell lines and in preclinical studies of non-human primates receiving porcine xenografts. Endogenous 'retroviral restriction factors' are intracellular proteins and components of the innate immune system that act at various steps in retroviral replication. Recent studies suggest that some of these factors may have applications in the management of endogenous retroviruses in xenotransplantation. The risks of PERV infection and the potential role of retroviral restriction factors in xenotransplantation are reviewed in detail.

Figures

Figure 1

The retroviral life cycle and sites of activity of the major antiviral restriction factors. Envelope glycoproteins of the retrovirus interact with specific host-cell membrane protein receptors. (1) The retroviral envelope fuses with the plasma membrane and enters the host cell. (2) Following fusion, the nucleocapsid enters the cytoplasm and (3) uncoating of viral core occurs. (4) Viral reverse transcriptase copies single strand viral RNA into double-stranded DNA. (5) Viral DNA is transported into the nucleus and integrated into host-cell chromosomal DNA. (6) Integrated viral DNA is transcribed by the host-cell RNA polymerase, generating mRNA molecules and new viral genomic RNA molecules [TRIM28 blocks viral transcription]. Viral mRNAs are translated into viral proteins (envelope, capsid, and reverse transcriptase). (7) Newly synthesized viral proteins and genomic RNA gather to form immature viral particles [ZAP degrades viral RNAs]. (8) New virions bud from the cell surface, acquiring an envelope including host-cellular and viral proteins from the cell membrane [Tetherin traps virions on the cell surface].