Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis.

Department of Internal Medicine and Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
European Journal of Clinical Investigation (Impact Factor: 2.83). 04/2002; 32 Suppl 1:91-6. DOI: 10.1046/j.1365-2362.2002.0320s1091.x
Source: PubMed

ABSTRACT BACKGROUNd: The iron chelators deferoxamine (DF) and deferiprone (CP20) have been shown to inhibit human immunodeficiency virus type 1 (HIV-1) replication in human peripheral blood lymphocytes (PBL). The orally active bidentate chelators CP502 and CP511, which also belong to the 3-hydroxypyridin-4-one family, but with higher affinities for iron than CP20, were monitored for their antiviral properties by checking for p24 antigen production and nuclear factor (NF)-kappaB activation, and their ability to induce apoptosis.
Human PBLs were isolated from HIV-1 seronegative donors and subsequently infected with HIV-1(Ba-L) for 2 h. After 5 days' incubation, HIV-1 replication was monitored by p24 antigen production. Cellular proliferation as well as caspase-3 activity were monitored in uninfected cells after a period of 5 days and after 1 day infection, respectively. NF-kappaB activity was also monitored by electromobility shift assays (EMSA) performed on nuclear extracts of Jurkat cells treated with the different chelators for 4 h.
CP502 and CP511 decrease HIV-1 replication by decreasing cellular proliferation in a similar manner to DF and CP20. CP511 seemed to be more potent than either CP502 or CP20. Due to the reduction in cellular proliferation, there was an increase in caspase-3 activity after 24 h incubation. NF-kappaB activity was not affected by any of the chelators.
Iron chelators with high affinities for iron, which are under development for the treatment of iron overload, could contribute to the reduction of HIV-1 replication in infected patients by cellular proliferation inhibition rather than by a direct antiviral action.


Available from: Joannes J M Marx, Jan 25, 2014