Cellular restriction factors and infectious risk by PERV

The life‐cycles of viruses depend on factors provided by host cells due to their limited genetic coding capacity (1). The permissiveness of a host cell is determined by restriction factors that evolved during host‐virus co‐evolution (2). Several restriction factors have been shown to be important for the replication of retroviruses: TRIM5α disrupts the viral capsid (CA) after cell entry; TRIM28 blocks viral transcription; ZAP (zinc finger antiviral protein) directs degradation of viral RNAs; tetherin traps virions on the surfaces of infected cells; and APOBEC (apolipoprotein B mRNA‐editing catalytic polypeptides) that are cytidine deaminases disrupts viral DNA during synthesis (2, 3). PERV‐A and recombinant PERV‐A/C are insensitive to restriction by TRIM5α in permissive feline cells expressing TRIMα proteins from humans, Africa green monkeys, rhesus macaques, squirrel monkeys, rabbits, or cattle (4). On the other hand, overexpression of either human or porcine tetherin in pig cells significantly reduced PERV production (5). The mammalian APOBEC3 (A3) genes are part of the AID/APOBEC gene family. Their members share structural and functional domains of zinc‐dependent deaminases (6). Proteins of the A3 group contain one or two zinc (Z)‐coordinating domains and are classified according to the presence/absence of a Z1, Z2, or Z3 motif (7, 8). Initial studies showed that porcine poA3Z2‐Z3 did not significantly interfere with PERV transmission (9) and it was concluded that PERV was resistant to its species‐specific A3 protein (10). Subsequently, the chromosomal porcine A3 locus for poA3Z2 and poA3Z3 was reanalyzed and data showed that pigs express four different A3 mRNAs, encoding poA3Z2 and poA3Z3 and, by readthrough transcription and alternative splicing, poA3Z2‐Z3 and poA3Z2‐Z3 splice variant A (SVA) (11, 12). Results illustrated that PERV was significantly inhibited by various porcine A3s in single‐round as well as spreading virus assays. PERV inhibition strongly correlated with a specific cytidine deamination in viral genomes for the trinucleotides 5′TGC, for poA3Z2 as well as poA3Z2‐Z3, and 5′CAC, for A3Z3 (11, 12). Data demonstrate that human and porcine A3s can inhibit PERV replication in vivo, thereby reducing the risk of potential infection of human cells by PERV in the course of pig‐to‐human xenotransplantation. References:  1. W atanabe T , W atanabe S , K awaoka Y . Cellular networks involved in the influenza virus life cycle. Cell Host Microbe 2010; 7: 427–439. 2. W olf D , G off SP . Host restriction factors blocking retroviral replication. Annu. Rev. Genet. 2008; 42: 143–163. 3. M eije Y , TÖ njes RR , F ishman JA . Retroviral restriction factors and infectious risk in xenotransplantation. Am. J. Transplant. 2010; 10: 1511–1516. 4. W ood A , W ebb BLJ , B artosch B , S challer T , T akeuchi Y , T owers GJ . Porcine endogenous retroviruses PERV A and A/C recombinant are insensitive to a range of divergent mammalian TRIM5a proteins including human TRIM5a. J. Gen. Virol. 2009; 90: 702–709. 5. M attiuzzo G , I vol S , T akeuchi Y . Regulation of porcine endogenous retrovirus release by porcine and human tetherins. J. Virol. 2010; 84: 2618–2622. 6. C onticello SG , T homas CJ , P etersen‐ M ahrt SK , N euberger MS . Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. Mol. Biol. Evol. 2005; 22: 367–377. 7. LARUE RS, ANDRÉSDÓTTIR V, BLANCHARD Y, CONTICELLO SG, DERSE D, EMERMAN M, GREENE WC, JÓNSSON SR, LANDAU NR, LÖCHELT M, MALIK HS, MALIM MH, MÜNK C, O’BRIEN SJ, PATHAK VK, STREBEL K, WAIN‐HOBSON S, YU XF, YUHKI N, HARRIS RS. Guidelines for naming nonprimate APOBEC3 genes and proteins. J. Virol. 2009; 83: 494–497. 8. MÜ nk C , B eck T , Z ielonka J , H otz‐ W agenblatt A , C hareza S , B attenberg M , T hielebein J , C ichutek K , B ravo IG , O’B rien SJ , LÖ chelt M , Y uhki N . Functions, structure, and read‐through alternative splicing of feline APOBEC3 genes. Genome Biol. 2008; 9: R48. 9. JÓ nsson SR , H ach ÉG , S tenglein MD , F ahrenkrug SC , A ndr É sd Ó ttir V , H arris RS . Evolutionarily conserved and non‐conserved retrovirus restriction activities of artiodactyl APOBEC3F proteins. Nucleic Acids Res. 2006; 34: 5683–5694. 10. JÓ nsson SR , L a R ue RS , S tenglein MD , F ahrenkrug SC , A ndr É sd Ó ttir V , H arris RS . The restriction of zoonotic PERV transmission by human APOBEC3G. PLoS One 2007; 2: e893. 11. DÖ rrschuck E , MÜ nk C , TÖ njes RR . APOBEC3 proteins and porcine endogenous retroviruses. Transplant. Proc. 2008; 40: 959 –961. 12. DÖ rrschuck E , F ischer N , B ravo IG , H anschmann KM , K uiper H , S p Ö tter A , MÖ ller R , C ichutek K , MÜ nk C , TÖ njes RR . Restriction of porcine endogenous retrovirus by porcine APOBEC3 cytidine deaminases. J. Virol. 2011; 85: 3842–3857.