Summary Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human IFN variants signal through the same cell surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique amongst the cytokine receptor superfamily, but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor-points" interspersed amongst ligand-specific interactions that ‘tune’ the relative IFN binding affinities, in an apparent extracellular ‘ligand proofreading’ mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that induce hyperproliferative lesions in epithelial tissues (42). A subset of HPV types infect epithelia in the anogenital region and are the etiological agents of cervical cancers. These HPV types are called "high-risk" and include HPV16, HPV18, HPV31, and HPV54 (37,43,72,73). The oncogenic potential of these high-risk types is dependent on the cooperative action of the two early viral gene products, E6 and E7, which bind and alter the activity of cell cycle-regulatory proteins. E6 forms a ternary complex composed of the tumor suppressor protein p53 and E6AP (E6-associated protein), a member of E3 ubiquitin ligase family of proteins, resulting in the ubiquitination and subsequent degradation of p53 (28,59,60,70). E7 binds to and inactivates the retinoblastoma (pRb) family of proteins, thereby alleviating the pRbmediated repression of E2F transcription factors that are responsible for transactivating many genes involved in progression into S phase (6,12,44,48). Selective retention and expression of these two viral oncoproteins is essential for HPVinduced oncogenesis (1, 2, 61, 62).The productive life cycle of HPVs is closely associated with the differentiation program of the host epithelial tissue (25). Following infection of keratinocytes in the basal layer, viral genomes are established in the nucleus as extrachromosomal elements (episomes). These episomes are replicated in synchrony with host DNA synthesis through the action of the early viral proteins, E1 and E2, and are maintained at approximately 50 copies per cell (38). As infected keratinocytes migrate away from the basal layer and begin to differentiate, they remain active in the cell cycle through the action of the E7 protein. In differentiated suprabasal cells, the induction of the late viral functions is observed (6,16,24). The differentiation-dependent amplification of viral genomes coincides with activation of the late viral promoter, which in HPV31 is called p742 (29). The late viral transcripts encode late viral proteins such as L1, L2, E1^E4, and E5 (10,17,58). Progeny virions are assembled in highly differentiated cells and then released to the extracellular environment (17,46).The targeting of p53 for degradation by E6 is the most extensively studied function of E6. However, a large amount of evidence suggests the existence of the p53-independent functions of E6 that are also necessary for transformation. Support for this idea comes from the observation that transformation of cells by E6 does not always correlate with its ability to degrade p53. For instance, several p53 degradation-defective E6 mutants are still able to immortalize mammary epithelial cells and transform 3Y1 rat fibroblasts (32, 41). In addition, activation of the human telomerase reverse transcriptase (hTERT) by E6 is more important for immortalization of epithelial cells than is inactivation of p53 (32, 34, 51). These observations indicate that E6 contributes to malignant conversion of HPV-infected cells th...

Virus-induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral diseases. In response to reactive oxygen species (ROS) generation by a virus, a host cell activates an antioxidative defense system for its own protection. Particularly, a nuclear factor erythroid 2p45-related factor 2 (Nrf2) pathway works in a front-line for cytoprotection and detoxification. Recently, a series of studies suggested that a group of clinically relevant viruses have the capacity for positive and negative regulations of the Nrf2 pathway. This virus-induced modulation of the host antioxidative response turned out to be a crucial determinant for the progression of several viral diseases. In this review, virus-specific examples of positive and negative modulations of the Nrf2 pathway will be summarized first. Then a number of successful genetic and pharmacological manipulations of the Nrf2 pathway for suppression of the viral replication and the pathogenesis-associated oxidative damage will be discussed later. Understanding of the interplay between virus-induced oxidative stress and antioxidative host response will aid in the discovery of potential antiviral supplements for better management of viral diseases.

Mammalian cells have evolved a unique strategy to protect themselves against oxidative damage induced by reactive oxygen species (ROS). Especially, two transcription factors, nuclear factor erythroid 2p45-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor γ (PPARγ), have been shown to play key roles in establishing this cellular antioxidative defense system. Recently, several researchers reported ameliorating effects of pharmacological activators for these Nrf2 and PPARγ pathways on the progression of various metabolic disorders and drug-induced organ injuries by oxidative stress. In this review, general features of Nrf2 and PPARγ pathways in the context of oxidative protection will be summarized first. Then, a number of successful applications of natural and synthetic Nrf2 and PPARγ activators to the alleviation of pathological and drug-related oxidative damage will be discussed later.

New classes of drugs are needed to combat hepatitis C virus (HCV), an important worldwide cause of liver disease. We describe an activity of a key domain, an amphipathic helix we termed 4BAH2, within a specific HCV nonstructural protein, NS4B. In addition to its proposed role in viral replication, we validate 4BAH2 as essential for HCV genome replication, and identify first generation small molecule inhibitors of 4BAH2 that specifically prevent HCV replication within cells. Detailed mechanistic studies reveal that the inhibitors target 4BAH2 function by either preventing 4BAH2 oligomerization or 4BAH2 membrane association. 4BAH2 inhibitors represent an exciting, additional class of compounds that has potential to effectively treat HCV.