EVIDENCE FOR A CONTINUED REQUIREMENT FOR CD40 CD40 LIGAND (CD154) INTERACTIONS IN THE PROGRESSION OF LP-BM5 RETROVIRUS-INDUCED MURINE AIDS/

In genetically susceptible C57BL/6 mice the LP-BM5 isolate of murine r etroviruses causes profound splenomegaly, lymphadenopathy, hypergammag lobulinemia, and an immunodeficiency syndrome bearing many similaritie s to the pathologies seen in AIDS. Because of these similarities, whic h also include terminal B cell lymphoma formation, this syndrome has b een called murine AIDS or MAIDS. Prompted by previous reports showing that the onset of MAIDS is dependent on the presence of both CD4(+) T and B cells, we have previously shown that anti-gp39/CD40 ligand mAb ( anti-CD40L mAb) treatment of LP-BM5-infected mice is effective in inhi biting the induction of MAIDS when a short course of anti-CD40L mAb tr eatment was started on the same day as LP-BM5 administration. The succ ess of anti-CD40L mAb therapy, as indicated by a much reduced degree o f splenomegaly, hypergammaglobulinemia, and mitogen and allogeneic CTL unresponsiveness, demonstrated that CD40L/CD40 interactions were crit ical to the establishment of MAIDS. Here we extend these findings thro ugh the use of delayed anti-CD40L mAb treatment of mice, beginning 3-4 weeks after LP-BM5 infection, by showing that interruption of CD40L/C D40 interactions also interferes with the progression of MAIDS. About 60% of LP-BM5-preinfected mice were affected by delayed anti-CD40L mAb treatment, with substantially reduced spleen weights and serum hyperg ammaglobulinemia and normal or greatly restored proliferative response s to Con A stimulation and CTL responses to allogeneic stimulation. Th e other LP-BM5-infected mice that did not respond to anti-CD40L therap y were found to have made antibodies to the anti-CD40L mAb. Thus, in a majority of mice anti-CD40L mAb therapy was very effective in interfe ring with MAIDS pathogenesis well after the establishment of the virus infection and MAIDS symptomatology, indicating that CD40L/CD40 intera ctions are crucial to the maintenance and progression of the disease, as well as its initiation. (C) 1998 Academic Press.