Anti-HIV effect of iron chelators: different mechanisms involved

Background: Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to sto p viral replication by inhibition of reverse transcriptase or protease acti vity. Studies showing that oxidative stress and iron may be important in th e activation of HIV-1 have focused attention on the potential therapeutic u se of iron chelators. Objectives: The goal of this review is to describe se veral possibilities as to how iron is involved in the replication of HIV an d how iron chelation may interfere in this process. Study design: First som e physico-chemical properties of iron concerning solubility, oxidation-redu ction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained. Results : Nuclear factor kappa B (NF-kappaB) activation, regulating proviral transc ription, can be influenced by iron through the production of reactive oxyge n species. A second route by which iron chelation could influence HIV repli cation, is by inhibition of DNA synthesis through inactivation of iron-depe ndent ribonucleotide reductase. Another strategy which can be employed in t argeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA at tack. This could be achieved by bleomycin, a cytostatic agent with the abil ity to form a complex with DNA and RNA. Conclusion: Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis o f reactive oxygen species directed to viral constituents. In combination wi th existing antivirals, iron chelation could add to improve the treatment o f HIV-disease. (C) 2001 Elsevier Science B.V. All rights reserved.