EFFICACY AND TOXICITY OF LONG-TERM ADMINISTRATION OF 2',3'-DIDEOXYCYTIDINE IN THE LP-BM5 MURINE-INDUCED IMMUNODEFICIENCY MODEL

The LP-BM5 murine retrovirus-induced immunodeficiency model was used to evaluate the efficacy and toxicity of long-term 2',3'-dideoxycytidine (DDC) therapy, A mean plasma drug concentration of 0.2 +/- 0.02 mu M of DDC for 3 months was found to reduce splenomegaly, lymphoadenopathy and hypergammaglobulinemia in infected mice, However, DDC also reduced spleen weight in control mice and spleen haemopoiesis in both infected and unifected animals. In the bone marrow the most prominent feature of DDC treatment was a marked reduction of megakariocytes, while in the liver an hepatocellular vacuolation was evident in uninfected animals. DDC reduced, but did not prevent, LP-BM5 integration in lymph node DNA and Pr 60(gag) expression in spleen lymphocytes and bone marrow cells, Furthermore, DDC reduced the mitochondrial DNA content and restored the mitogen proliferation of T cells but not that of B cells in infected mice. Thus, DDC appears to be of some, but limited, efficacy in murine AIDS, with a toxicity profile involving more cell types than previously thought.