Mechanism of Host Defense Suppression Induced by Viral Infection: Mode of Action of Inosiplex as an Antiviral Agent

Abstract

The mechanism of influenza virus (INFV)-induced immunosuppression and the mode of inosiplex action against INFV infection were studied. INFV suppressed both anti-lipopolysaccharide and anti-sheep erythrocyte antibody production in mice. INFV infection caused viral mRNA synthesis and increased total RNA synthesis in lymphocytes, but total mRNA synthesis was decreased. The translational ability of INFV-infected lymphocytes was also suppressed. Thus, INFV seemed to cause suppression of both mRNA synthesis and the translational ability of lymphocytes, resulting in suppression of lymphocyte functions. Inosiplex potentiated antibody production against sheep erythrocytes but not against lipopolysaccharide in normal and INFV-infected mice. Adamantanamine did not produce such a potentiating effect. The lymphocytes obtained from INFV-immunized and inosiplex-treated mice conferred resistance against INFV infection. This resistance was partially inhibited by anti-Thy 1.2 antibody treatment of the lymphocytes. In an adoptive cell transfer system, inosiplex treatment of T-cell donors potentiated antibody production when a non-immunosuppressive carrier (human serum albumin) was used. When an immunosuppressive carrier (INFV) was used, inosiplex treatment of either B-cell donors or T-cell donors increased antibody production. Direct introduction of inosiplex into lymphocytes by a cell fusion technique stimulated anti-sheep erythrocyte antibody production more effectively than the addition of inosiplex to cultures. Inosiplex increased total RNA and total mRNA syntheses in phytohemagglutinin-treated lymphocytes. In INFV-infected lymphocytes, inosiplex decreased syntheses of total RNA, total mRNA, and viral mRNA and restored translational ability. From these results, we concluded that inosiplex penetrates into lymphocytes and suppresses viral RNA synthesis and that it supports lymphocyte functions by promoting RNA synthesis and translational ability, both of which are necessary for hosts.