Intracellular Chelation of Iron by Bipyridyl Inhibits DNA Virus Replication

Abstract

The efficient replication of large DNA viruses requires dNTPs supplied by a viral ribonucleotide reductase. Viral ribonucleotide reductase is an early gene product of both vaccinia and herpes simplex virus. For productive infection, the apoprotein must scavenge iron from the endogenous, labile iron pool(s). The membrane-permeant, intracellular Fe 2؉ chelator, 2,2-bipyridine (bipyridyl, BIP), is known to sequester iron from this pool. We show here that BIP strongly inhibits the replication of both vaccinia and herpes simplex virus, type 1. In a standard plaque assay, 50 M BIP caused a 50% reduction in plaque-forming units with either virus. Strong inhibition was observed only when BIP was added within 3 h post-infection. This time dependence was observed also in regards to inhibition of viral late protein and DNA synthesis by BIP. BIP did not inhibit the activity of vaccinia ribonucleotide reductase (RR), its synthesis, nor its stability indicating that BIP blocked the activation of the apoprotein. In parallel with its inhibition of vaccinia RR activation, BIP treatment increased the RNA binding activity of the endogenous iron-response protein, IRP1, by 1.9-fold. The data indicate that the diiron prosthetic group in vaccinia RR is assembled from iron taken from the BIP-accessible, labile iron pool that is sampled also by ferritin and the iron-regulated protein found in the cytosol of mammalian cells.

Expression of iron‐related proteins during infection by bovine herpes virus type‐1

“…In this context, ferritin is the more efficient one and induction of this protein, that acts as an effective Fe 2þ scavenger by its ability to sequester up to 4,500 iron ions per molecule [Theil, 2004], might interfere with the virus replication by sequestering iron from the endogenous 'LIP' and by reducing iron availability to assemble functional viral RR. A similar effect is observed when membrane-permeant strong iron chelators, such as bipyridyl (BIP) and salicylaldehyde isonicotinoyl hydrazone (SIH), are added to in vitro experiments in a standard plaque assay [Romeo et al, 2001]. An increase of ferritin expression has been also reported by Mulvey et al [1996] in the mengo virus infections, and more recently the increase of ferritin expression has been correlated with the integrity of the casein kinase II phosphorylation site of the mengo virus leader protein [Zoll et al, 2002].…”

Phytoplankton Virus Production Negatively Affected by Iron Limitation

“…Then again, F v /F m of P. globosa cells prior to infection was reduced compared to Fereplete, still not prolonging the latent period. We cannot be sure of the exact underlying mechanism from the here presented data, but the proliferation of DNA viruses is directly dependent on Fe due to the essential role Fe plays in the catalytic center of ribonucleotide reductase, produced early in infection to support dNTPs production needed for viral DNA synthesis (Romeo et al, 2001). As such, it can be speculated that not the time to produce a virus is affected but instead the number of viruses that can be produced before cell lysis occurs.…”

Iron loading into ferritin can be stimulated or inhibited by the presence of cations and anions: A specific role for phosphate

“…Iron is also essential for the reproduction of DNA viruses. Viral ribonucleotide reductase requires iron scavenged from the hostÕs intracellular iron pool, to produce a functional ribonucleotide reductase enzyme for viral genomic replication [3][4][5]. The essential requirement for iron necessitates that biological mechanisms exist to recognize, bind and transport iron into the cell.…”