Abstract
Alpha- and flaviviruses contain class II fusion proteins, which form ion-permeable pores in the target membrane during virus entry. The pores generated during entry of the alphavirus Semliki Forest virus have been shown previously to be blocked by lanthanide ions. Here, analyses of the influence of rare earth ions on the entry of the flaviviruses West Nile virus and Uganda S virus revealed an unexpected effect of lanthanide ions. The results showed that a 30 s treatment of cells with an appropriate lanthanide ion changed the cellular chemistry into a state in which the cells no longer supported the multiplication of flaviviruses. This change occurred in cells treated before, during or after infection, did not inhibit multiplication of Semliki Forest virus and did not interfere with host-cell multiplication. The change was generated in vertebrate and insect cells, and was elicited in the presence of actinomycin D. In vertebrate cells, the change was elicited specifically by La3+, Ce3+, Pr3+ and Nd3+. In insect cells, additional lanthanide ions had this activity. Further analyses showed that lanthanide ion treatment blocked the ability of the host cell to support the replication of flavivirus RNA. These results open two areas of research: the study of molecular alterations induced by lanthanide ion treatment in uninfected cells and the analysis of the resulting modifications of the flavivirus RNA replicase complex. The findings possibly open the way for the development of a general chemotherapy against flavivirus diseases such as Dengue fever, Japanese encephalitis, West Nile fever and yellow fever.
Highlights
Entry of enveloped viruses involves fusion of the envelope with a target membrane
We have previously shown that lanthanide ions block the ion pores generated during entry of alphaviruses at the plasma membrane without interfering with productive infection (Koschinski et al, 2005)
As similar ion-permeable pores are generated during entry of the flavivirus West Nile virus (WNV) (Koschinski et al, 2003), we analysed the effect of lanthanide ions on the establishment of a productive infection by flaviviruses
Summary
Entry of enveloped viruses involves fusion of the envelope with a target membrane. This reaction is regulated by viral fusion proteins. The fusion proteins of alphaviruses (family Togaviridae; reviewed by Schlesinger & Schlesinger, 2001) and flaviviruses (family Flaviviridae; reviewed by Lindenbach & Rice, 2001) are class II fusion proteins These proteins have two additional functions: they generate an icosahedral lattice on the viral surface (Lescar et al, 2001; Pletnev et al, 2001) and they form ion-permeable pores in the target membrane during virus entry (Carrasco, 1995; Nyfeler et al, 2001; Wengler et al, 2003). As similar ion-permeable pores are generated during entry of the flavivirus West Nile virus (WNV) (Koschinski et al, 2003), we analysed the effect of lanthanide ions on the establishment of a productive infection by flaviviruses. The results of these studies are reported in this paper
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