Inhibition of murine AIDS by alternate administration of azidothymidine and fludarabine monophosphate

Anti-HIV-l combination therapies, including protease and reverse transcript ase inhibitors, can reduce plasma viremia to undetectable levels within the first 2 weeks of treatment. This reduction is followed by a slower decline that primarily results from the presence of viral reservoirs such as CD4() memory cells, dendritic cells, and macrophages. For this reason, we evalu ated a new drug combination therapy that includes a lympholytic drug: (2-fl uoro-ara-AMP, fludarabine) to eliminate cells already infected and an antiv iral drug (azidothymidine [AZT]) to protect cells not yet infected. We used C57BL/6 mice infected with the retroviral complex LP-BMS, which developed severe immunodeficiency (i.e., murine AIDS), to select the most effective f ludarabine regimen to inhibit disease progression, and then to evaluate the efficacy and toxicity of the fludarabine and AZT combinations. The results obtained show that intraperitoneal administration of fludarabine at 3 mg/m ouse twice a day for 4 weeks is the most effective regimen in reducing sple nomegaly, lymphadenopathy, hypergammaglobulinemia, and proviral DNA content in spleen and lymph nodes and in restoring the architecture of lymph nodes . Subsequently, we evaluated the combined or sequential administration of f ludarabine and AZT. The data reported in this paper show that the sequentia l administration of the two drugs provides additive antiviral effects that reduce spleen and lymph node weights to normal values and proviral DNA cont ent by approximate to 95% in all infected organs; the phenotypes of blood T and B cells moved toward control values, although the number of B cells wa s significantly reduced by fludarabine treatment. Finally, we evaluated the outcome of the disease after suspension or continuation of different treat ment regimens. In all treatment groups, the disease progressed and increase d proviral DNA content was found in infected organs, but animals receiving the sequential administration of fludarabine and AZT were less affected tha n those receiving only fludarabine or the simultaneous administration of bo th. The results obtained suggest that fludarabine could be part of a new th erapeutic approach aiming at eradicating HIV from those cells that have bee n already infected and that are not protected by highly active antiretrovir al therapy (HAART).