Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted by Aedes mosquitoes. Infection with CHIKV elicits a type I interferon response that facilities virus clearance, probably through the action of down-stream effectors such as antiviral IFN-stimulated genes (ISGs). Bone marrow stromal antigen 2 (BST-2) is an ISG shown to restrict HIV-1 replication by preventing the infection of bystander cells by tethering progeny virions on the surface of infected cells. Here we show that enrichment of cell surface BST-2 results in retention of CHIKV virus like particles (VLPs) on the cell membrane. BST-2 was found to co-localize with CHIKV structural protein E1 in the context of VLPs without any noticeable effect on BST-2 level. However, CHIKV nonstructural protein 1 (nsP1) overcomes BST-2-mediated VLPs tethering by down-regulating BST-2 expression.. We conclude that BST-2 tethers CHIKV VLPs on the host cell plasma membrane and identify CHIKV nsP1 as a novel BST-2 antagonist.

BackgroundBone marrow stromal cell antigen 2 (BST-2) is a cellular factor that restricts the egress of viruses such as human immunodeficiency virus (HIV-1) from the surface of infected cells, preventing infection of new cells. BST-2 is variably expressed in most cell types, and its expression is enhanced by cytokines such as type I interferon alpha (IFN-α). In this present study, we used the beta-retrovirus, mouse mammary tumor virus (MMTV) as a model to examine the role of mouse BST-2 in host infection in vivo.ResultsBy using RNA interference, we show that loss of BST-2 enhances MMTV replication in cultured mammary tumor cells and in vivo. In cultured cells, BST-2 inhibits virus accumulation in the culture medium, and co-localizes at the cell surface with virus structural proteins. Furthermore, both scanning electron micrograph (SEM) and transmission electron micrograph (TEM) show that MMTV accumulates on the surface of IFNα-stimulated cells.ConclusionsOur data provide evidence that BST-2 restricts MMTV release from naturally infected cells and that BST-2 is an antiviral factor in vivo.

Herpes simplex virus 1 (HSV-1) capsids leave the nucleus by a process of envelopment and de-envelopment at the nuclear envelope (NE) that is accompanied by structural alterations of the NE. As capsids translocate across the NE, transient primary enveloped virions form in the perinuclear space. Here, we provide evidence that torsinA (TA), a ubiquitously expressed ATPase, has a role in HSV-1 nuclear egress. TA resides within the lumen of the endoplasmic reticulum (ER)/NE and functions in maintaining normal NE architecture. We show that perturbation of TA normal function by overexpressing torsinA wild type ( Following capsid assembly and DNA packaging, herpesvirus DNA-containing capsids in the nucleus translocate through the nuclear envelope (NE) into the cytoplasm by envelopment at the inner nuclear membrane (INM), followed rapidly by deenvelopment at the outer nuclear membrane (ONM). Between envelopment and de-envelopment, enveloped capsids called primary virions reside briefly in the perinuclear space that is contiguous with the lumen of the endoplasmic reticulum (ER) (reviewed in reference 34).Nuclear envelopment requires expression of the viral pUL31 and pUL34 (7,14,27,44,48). These proteins form a complex that is targeted to the NE and anchored in the membrane by the transmembrane domain of pUL34 (44,45,64,65). The pUL34/ pUL31 complex coordinates multiple events in nuclear egress, including disruption of the nuclear lamina, selection of DNAcontaining capsids for envelopment, budding of capsids into the INM, and de-envelopment and release of capsids at the ONM (2,30,38,43,46,53). pUL31 and pUL34 are incorporated into the perinuclear virion and are ordinarily lost from the egressing capsid upon de-envelopment at the ONM (14, 27, 31, 42, 45). Thus, they are not associated with cytoplasmic egress intermediates or with the mature virion that is released from the cell.De-envelopment may be inhibited and/or delayed by mutations in several herpes simplex virus (HSV) gene products. Mutations that eliminate either the expression or kinase activity of pUS3 result in accumulation of primary virions in the perinuclear space. During infection with these mutants, the perinuclear space expands by bulging into the nucleoplasm, perhaps because the exaggerated disruption of the nuclear lamina associated with loss of pUS3 function makes this the path of least resistance (2, 28, 36-38, 45, 49). A de-envelopment defect is also observed in cells infected with recombinant mutants of HSV-1 that fail to express both of the envelope glycoproteins gB and gH (13).Infection with HSV-1 alters the morphology and structure of the NE. The nucleus expands and changes shape. In addition, redistribution of nuclear lamina proteins is observed, most likely due to phosphorylation-mediated loss of protein-protein interactions (2,30,35,36,43,49,50,53,54). In addition to these changes, formation of perinuclear primary virions is likely to be accompanied by alteration of interactions that maintain spacing between the INM and ONM.The product of the DYT...

Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3–4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1’s function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.

Herpesvirus infection reorganizes components of the nuclear lamina usually without loss of integrity of the nuclear membranes. We report that wild-type HSV infection can cause dissolution of the nuclear envelope in transformed mouse embryonic fibroblasts that do not express torsinA. Nuclear envelope breakdown is accompanied by an eight-fold inhibition of virus replication. Breakdown of the membrane is much more limited during infection with viruses that lack the gB and gH genes, suggesting that breakdown involves factors that promote fusion at the nuclear membrane. Nuclear envelope breakdown is also inhibited during infection with virus that does not express UL34, but is enhanced when the US3 gene is deleted, suggesting that envelope breakdown may be enhanced by nuclear lamina disruption. Nuclear envelope breakdown cannot compensate for deletion of the UL34 gene suggesting that mixing of nuclear and cytoplasmic contents is insufficient to bypass loss of the normal nuclear egress pathway.

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