Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)-induced lymphoproliferative disease and lytic viral replication

Abstract

EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both “on target” and “off target” mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

“…Some of the KSHVassociated malignancies, like Kaposi sarcoma, seem to depend on lytic replication of this virus 123 . Targeting of early lytic antigen expression might provide a promising novel strategy for the treatment of both EBV and KSHV associated tumors 124 .…”

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…LEF can significantly reduce CMV-induced apoptosis of the infected cells, interfering with the spreading of the virus [111]. Bilger et al showed that teriflunomide can have a role against Epstein-Barr virus (EBV) [112]. Drug concentrations lower than those normally used for treatment of RA can prevent EBVtransformed human B cell proliferation thanks to an "on target" mechanism on B cells and an "off target" action that alter EBV latency protein expression.…”

“…Drug concentrations lower than those normally used for treatment of RA can prevent EBVtransformed human B cell proliferation thanks to an "on target" mechanism on B cells and an "off target" action that alter EBV latency protein expression. In fact, an increased expression of EBV nuclear antigen-2 (EBNA2) and latent membrane protein-1 (LMP1), the latter able to inhibit B cell proliferation, were observed [112]. Furthermore, teriflunomide induces expression of p53 and cleavage level of PARP, promoting apoptosis of lymphocytes in vitro.…”

“…No reduction of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) signaling by teriflunomide was reported in this setting. The drug can inhibit lytic EBV infection in vitro by preventing the initial steps of lytic viral reactivation by reducing immediate-early lytic protein and early lytic protein expression, in response to B-cell receptor, and by blocking lytic viral DNA replication [112].…”

COVID-19 in Teriflunomide-Treated Patients with Multiple Sclerosis

“…In addition, there is emerging evidence suggesting a direct antiviral effect for teri unomide and other DHODH inhibitors against a range of viruses such as Theiler's, virulent Newcastle disease, respiratory syncytial, Ebola, cytomegalovirus, Epstein-Barr, and picornavirus (foot-and-mouth disease) [25][26][27][28]. Moreover, a preliminary pre-clinical study suggests that teri unomide could combat COVID-19 though dual antiviral and immunomodulatory actions [29].…”