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 stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators.


OBJECTIVE
The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process.


METHODS
First some physico-chemical properties of iron concerning solubility, oxidation-reduction 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 transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA.


CONCLUSIONS
Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.
van Asbeck
B S
BS
Department of Internal Medicine, University Hospital Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. b.s.vanasbeck@digd.azu.nl
Georgiou
N A
NA
van der Bruggen
T
T
Oudshoorn
M
M
Nottet
H S
HS
Marx
J J
JJ
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004279:DNA, Viral / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D012367:RNA, Viral / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D004279:DNA, Viral; D007502:Iron Chelating Agents; D016328:NF-kappa B; D012367:RNA, Viral; D007501:Iron