Antiviral activity of immunosuppressors alone and in combination against human adenovirus and cytomegalovirus

Abstract

Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC₅₀) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC₅₀=0.05 µM and 0.3 µM, respectively) and HCMV (IC₅₀=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI₅₀) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI₅₀=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI₅₀=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human C_max values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.

Keywords: Adenovirus; Antiviral; Cyclophosphamide; Cyclosporine; Cytomegalovirus; Everolimus; Immunosuppressive therapy; Methotrexate; Mycophenolic; Sirolimus; Tacrolimus.