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

Abstract

Anti-HIV-1 combination therapies, including protease and reverse transcriptase 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 evaluated a new drug combination therapy that includes a lympholytic drug: (2-fluoro-ara-AMP, fludarabine) to eliminate cells already infected and an antiviral drug (azidothymidine [AZT]) to protect cells not yet infected. We used C57BL/6 mice infected with the retroviral complex LP-BM5, which developed severe immunodeficiency (i.e., murine AIDS), to select the most effective fludarabine 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/mouse twice a day for 4 weeks is the most effective regimen in reducing splenomegaly, 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 fludarabine and AZT. The data reported in this paper show that the sequential administration of the two drugs provides additive antiviral effects that reduce spleen and lymph node weights to normal values and proviral DNA content by approximately 95% in all infected organs; the phenotypes of blood T and B cells moved toward control values, although the number of B cells was significantly reduced by fludarabine treatment. Finally, we evaluated the outcome of the disease after suspension or continuation of different treatment regimens. In all treatment groups, the disease progressed and increased proviral DNA content was found in infected organs, but animals receiving the sequential administration of fludarabine and AZT were less affected than those receiving only fludarabine or the simultaneous administration of both. The results obtained suggest that fludarabine could be part of a new therapeutic approach aiming at eradicating HIV from those cells that have been already infected and that are not protected by highly active antiretroviral therapy (HAART).