HCV is a positive-sense, single-stranded RNA virus that is packaged into an enveloped virus particle (Dustin and Rice2007; Randall and others2007). combat invading microbes (Biron2001; Samuel2001; Barnes and others2002). The type I interferons (IFNs) are among the earliest of these defenses. The importance of type I IFNs is usually highlighted by the enhanced susceptibility of IFN-/R-deficient mice to virus contamination (Kamijo and others1994; Hwang and others1995) and the myriad of strategies employed by viruses to interfere with their production and/or action and the antiviral activity of the IFN-stimulated genes (ISGs) themselves [reviewed in (Katze and others2002)]. The workhorses of the type I IFN system are these ISGs, several of which have been characterized in detail. The mechanisms by which ISGs restrict viral replication are ill-defined and are covered in this issue. Viperin is usually one such example. The results of gene-profiling microarray studies showed that this Viperin gene is usually one of those that is often most highly induced by a range of different viruses (Boudinot and others2000; Sun and Nie2004; Helbig and others2005; Olofsson and others2005; Severa and others2006; Chan and others2008), by the double-stranded RNA analog poly(I-C) (Severa and others2006), by Gentamycin sulfate (Gentacycol) the double-stranded B-form DNA (poly-dAdT) (Kato and others2006) and by microbial products, such as lipopolysaccharide (Olofsson and others2005; Severa and others2006), in various cell types. While considerable progress has been made in our understanding of how Viperin is usually turned on in cells, key mechanistic insights into its mode of action are only beginning to be elucidated. Viperin (virus inhibitory protein, endoplasmic reticulum [ER]-associated, IFN-inducible) was first identified in fish, as virus induced gene (vig1), where it was shown to be induced to high levels during contamination of rainbow trout leukocytes with viral hemorrhagic septicemia virus, a fish rhabdovirus (Boudinot and others2000). Its human homolog, cytomegalovirus-induced gene (cig5) [also known as radical Gentamycin sulfate (Gentacycol) S-adenosyl methionine (SAM) domain-containing 2 in both human and mouse], was similarly identified from primary skin cultures incubated with inactivated human cytomegalovirus (HCMV). While examining the IFN- response of human macrophages, Chin and Cresswell (2001) identified a unique IFN- inducible gene, fragments of which were identical to cig5, which they subsequently named Viperin. The amino acid sequence of Viperin was then found to be homologous to a rat gene, interferon-inducible gene expressed during bone formation (BEST5), expressed during rat osteoblast differentiation. Viperin has since been found in a wide range of organisms ranging from bony fish to mammals (Fig. 1). Although IFN- was capable of inducing expression of Viperin, the type I IFNs were far more potent activators. Additional studies revealed the ability HLA-G of human cytomegalovirus as well as the HCMV glycoprotein B (gB) protein to potently upregulate Viperin gene expression (Chin and Cresswell2001). == FIG. 1. == Phylogenetic tree showing the evolutionary conservation of RSAD2 (Viperin)(a)and the domain Gentamycin sulfate (Gentacycol) name organization of the human Viperin gene(b). RSAD2, radical S-adenosyl methionine domain-containing 2. The initial characterization of Viperin revealed its ability to prevent the replication of HCMV. Over the last several years, Viperin has been shown to have activity against a range of additional viruses, including influenza virus, hepatitis C virus (HCV), dengue virus, alphaviruses, and retroviruses such as human immunodeficiency virus. The mechanism by which Viperin restricts replication of all of these viruses is not fully clear. In the case of HCMV, it was shown that while ectopic expression of Viperin in fibroblasts had no effect on HCMV immediate early viral gene expression (IE1 and IE2), the synthesis of early late, (pp65), late (gB), or true late (pp28) genes was significantly reduced in cells expressing Viperin compared to control cells. Since expression of these proteins is usually indispensible for productive HCMV contamination, these studies indicated that Viperin likely exerted its antiviral effects at a late stage in of the viral life cycle (Chin and Cresswell2001). The human.