TRIM5α restricts poxviruses and is antagonized by CypA and viral protein C6

Human tripartite motif protein 5a (TRIM5α) is a well-characterised restriction factor for some RNA viruses including HIV, but against DNA viruses reports are limited. Here, we demonstrate TRIM5α also restricts orthopoxviruses and, via its SPRY domain, binds the orthopoxvirus capsid protein L3 to diminish virus replication and activate innate immunity. In response, several orthopoxviruses, including vaccinia, rabbitpox, cowpox, monkeypox, camelpox and variola viruses, deploy countermeasures. First, protein C6 binds to TRIM5 via the RING domain to induce its proteasome-dependent degradation. Second, cyclophilin A (CypA) is recruited via interaction with capsid protein L3 to virus factories and virions to antagonise TRIM5α, and this interaction is prevented by cyclosporine A (CsA) and non-immunosuppressive derivatives alisporivir and NIM811. Both the proviral effect of CypA and antiviral effect of CsA are TRIM5α-dependent. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses and since these drugs target a cellular protein, CypA, emergence of virus drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses including monkeypox and variola.