Replication Of Enveloped Viruses Research Articles

Cutting Edge: Paradoxical Roles of BST2/Tetherin in Promoting Type I IFN Response and Viral Infection

Bone marrow stromal Ag 2 (BST2) is a transmembrane protein that prevents virus release from infected cells. It was also reported that BST2 inhibits type I IFN production by plasmacytoid dendritic cells. To determine BST2 impact on antiviral responses in vivo, we generated BST2(-/-) mice. Following infection with a murine retrovirus, BST2(-/-) mice had slightly elevated viral loads; however, infection with other enveloped viruses revealed unexpected roles of BST2. BST2(-/-) mice showed reduced type I IFN production by plasmacytoid dendritic cells. Moreover, BST2(-/-) mice had lower viral titers in lungs following intranasal infection with vesicular stomatitis virus expressing OVA and influenza B and increased numbers of virus-specific CD8 T cells in the lungs, suggesting that BST2 may facilitate entry and/or replication of enveloped viruses and modulate priming of CD8 T cells. These findings suggest complex roles of BST2 beyond retroviral control in vivo, possibly reflecting the involvement of BST2 in endocytosis and intracellular trafficking of viruses, viral nucleic acids, and Ags.

Membrane Fusion and Fission: Enveloped Viruses

Membrane fusion and fission are two key processes that occur during the replication of enveloped viruses, namely access to the interior of the host-cell (entry, which requires fusion of the viral envelope with the target cell envelope) and dissemination of viral progeny after replication (egress, which involves budding and fission). These dynamic processes are mediated by specialized proteins that modify and bend the lipid bilayer transiently and locally. This review focuses on fusion and fission reactions and on the hypothetical shared mechanism that generates their driving force.

A host cell membrane protein, golgin-97, is essential for poxvirus morphogenesis

Acquisition of the membrane and genome encapsidation is an important step in the replication of enveloped viruses. The biogenesis of the poxviral primary membrane and the core as well as the mechanisms of their maturation are poorly understood. Using RNA interference approach, we demonstrate that a cellular trans-Golgi network membrane protein, golgin-97, is essential for virus replication. Analysis of the virion morphology in the cells depleted of golgin-97 shows that the protein is required for the virus morphogenesis and, in particular, for the formation of the first infectious virus form, mature virus, but not its precursor, immature virus. This suggests that golgin-97 may be involved in the maturation of the virus core and, potentially, the virus membrane.

Antiparasitic effects of the intra-Golgi transport inhibitor megalomicin.

The macrolide antibiotic megalomicin (MGM) has been shown to inhibit vesicular transport between the medial- and trans-Golgi, resulting in the undersialylation of cellular proteins (P. Bonay, S. Munro, M. Fresno, and B. Alarcón, J. Biol. Chem. 271:3719-3726, 1996). Due to the effects of MGM on the Golgi and on the replication of enveloped viruses, we decided to test whether it has any antiparasitic activity. The results showed that MGM has potent activity against the epimastigote stage of Trypanosoma cruzi, producing a 50% inhibitory concentration (IC50) of 0.2 microg/ml. Furthermore, MGM was also active against the intracellular replicative, amastigote form of T. cruzi, completely preventing its replication in infected murine LLC/MK2 macrophages at a dose of 5 microg/ml. Although less potent, MGM was also active against Trypanosoma brucei epimastigotes (IC50, 2 microg/ml) and Leishmania donovani and Leishmania major promastigotes (IC50, 3 and 8 microg/ml, respectively). MGM also blocked intracellular replication of the asexual stage of Plasmodium falciparum-infected erythrocytes at 1 microg/ml. Finally, MGM was active in an in vivo model, resulting in the complete protection of BALB/c mice from death caused by acute T. brucei infection and significantly reducing the parasitemia. These results suggest that MGM is a potential drug for the treatment of veterinary and human parasitic diseases.

Inhibitory Effects of Polycations on the Replication of Enveloped Viruses (HIV, HSV, CMV, RSV, Influenza A Virus and Togaviruses)in vitro

Polycationic compounds, i.e. poly-l-lysines and poly-d-lysines, were evaluated for their in vitro effect on the replication of various viruses. Poly-l-lysines of different molecular weight proved inhibitory to the replication of several enveloped viruses, such as human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), respiratory syncytial virus (RSV), influenza A virus, Sindbis virus, Semliki Forest virus, vesicular stomatitis virus (VSV), herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (CMV). The mechanism of action of the polylysines against HIV-1, RSV and CMV could be attributed to an inhibitory effect on virus binding to the host cells, as demonstrated by an indirect immunofluorescence/laser flow cytofluorographic method, virus plaque reduction and measurement of radiolabelled virion association with the cells, respectively.

Modulation of glycosylation and transport of viral membrane glycoproteins by a sodium ionophore.

Analysis of viral glycoprotein expression on surfaces of monensin-treated cells using a fluorescence-activated cell sorter (FACS) demonstrated that the sodium ionophore completely inhibited the appearance of the vesicular stomatitis virus (VSV) G protein on (Madin-Darby canine kidney) MDCK cell surfaces. In contrast, the expression of the influenza virus hemagglutinin (HA) glycoprotein on the surfaces of MDCK cells was observed to occur at high levels, and the time course of its appearance was not altered by the ionophore. Viral protein synthesis was not inhibited by monensin in either VSV- or influenza virus-infected cells. However, the electrophoretic mobilities of viral glycoproteins were altered, and analysis of pronase-derived glycopeptides by gel filtration indicated that the addition of sialic acid residues to the VSV G protein was impaired in monensin-treated cells. Reduced incorporation of fucose and galactose into influenza virus HA was observed in the presence of the ionophore, but the incompletely processed HA protein was cleaved, transported to the cell surface, and incorporated into budding virus particles. In contrast to the differential effects of monensin on VSV and influenza virus replication previously observed in monolayer cultures of MDCK cells, yields of both viruses were found to be significantly reduced by high concentrations of monensin in suspension cultures, indicating that cellular architecture may play a role in determining the sensitivity of virus replication to the drug. Nigericin, an ionophore that facilitates transport of potassium ions across membranes, blocked the replication of both influenza virus and VSV in MDCK cell monolayers, indicating that the ion specificity of ionophores influences their effect on the replication of enveloped viruses.

Über biologische Wirkungen von Koordinationsverbindungen der Übergangsmetalle 2. Zur antiviralen Wirkung von 4-Methyl-2-amino-pyridin-palladiumchlorid (IV)

Abstract 4-methyl-2-amino-pyridine-palladiumchlorid (IV) showed an inactivation of cell-free enveloped DNA and RNA viruses in serum-free saline such as vaccinia, Pseudorabies, herpes type 1, Newcastle disease and influenza virus A/fowl plague, human influenza type A and B and vesicular stomatitis viruses, and adenovirus, a naked DNA virus, too. Picorna viruses were not inactivated, the inactivation of other viruses failed in medium with 10% serum. However the replication of enveloped viruses as checked with vaccinia and fowl plague viruses was inhibited, also when the compound was present only for 1 h after infection. Contrary to this the multiplication of adenovirus was depressed only with 90%. For the inactivation of viruses higher concentrations were necessary than for the inhibition of replication. Therefore more than one kind of mode of action have to be taken into consideration.

True Mediterranean Fever in England

Bone marrow stromal Ag 2 (BST2) is a transmembrane protein that prevents virus release from infected cells. It was also reported that BST2 inhibits type I IFN production by plasmacytoid dendritic cells. To determine BST2 impact on antiviral responses in vivo, we generated BST2^−/− mice. Following infection with a murine retrovirus, BST2^−/− mice had slightly elevated viral loads; however, infection with other enveloped viruses revealed unexpected roles of BST2. BST2^−/− mice showed reduced type I IFN production by plasmacytoid dendritic cells. Moreover, BST2^−/− mice had lower viral titers in lungs following intranasal infection with vesicular stomatitis virus expressing OVA and influenza B and increased numbers of virus-specific CD8 T cells in the lungs, suggesting that BST2 may facilitate entry and/or replication of enveloped viruses and modulate priming of CD8 T cells. These findings suggest complex roles of BST2 beyond retroviral control in vivo, possibly reflecting the involvement of BST2 in endocytosis and intracellular trafficking of viruses, viral nucleic acids, and Ags.