PERV induces CXCL10 in human monocytes and monocyte-derived primary cells

Abstract

Introduction: Pigs are suitable donor species for xenotransplantation and biological materials from these animals are used for this purpose for many years. A major risk of xenotransplantation is a zoonosis by transspecies transmission of animal viruses. In this regard Porcine Endogenous Retroviruses (PERVs) are of paramount importance because some of them are able to infect human cells and could induce innate immune responses. Methods: Using a replication competent polytropic PERV-A/C strain we have analysed induction of innate immune responses by this virus in human monocytes, Monocyte-Derived Macrophages (MDM) and Monocyte-Derived Dendritic Cells (MDDC). Results: PERV-A/C elevates expression of the C-X-C motif chemokine 10 (CXCL10) up to 1000-fold in human monocytes and monocyte-derived primary cells. In comparison to CXCL10, the levels of interferon-β (IFN-β) and Interferon-Stimulated Gene 54 (ISG54) were almost unchanged. Heat-inactivated virus did not induce CXCL10 expression. Neither treatment with the reverse transcriptase inhibitors azidothymidine (AZT) and stavudine (d4T) nor treatment with the integrase inhibitor raltegravir (RAL) reduced the activation levels. Furthermore, depletion of SAM domain and HD domain-containing protein 1 (SAMHD1), a restriction factor that blocks PERV-A/C infection at the level of reverse transcription in these myeloid cells, had no significant effect on the CXCL10 induction level. These results imply that innate immune sensing leading to the strong CXCL10 response occurs at an early step of the replication process and does not require products of reverse transcription. Inhibition of Janus Kinases (JAKs) by AT9283 prevented the observed CXCL10 induction by the virus providing evidence that the JAK-STAT signalling pathway is involved in the CXCL10 response in theses myeloid cells. Conclusion: Our findings highlight PERVs as inducers of the pro-inflammatory chemokine CXCL10 and other innate immune responses in human monocytes and derived cells with potential implications in the context of xenotransplantation.