Biologically significant interaction of human herpesvirus 8 viral interferon regulatory factor 4 with ubiquitin-specific protease 7.

Unlabelled: Human herpesvirus 8 (HHV-8), associated with Kaposi sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman disease, encodes four interferon regulatory factor homologs, vIRFs 1-4, that interact with and inhibit various mediators of host-cell defense against virus infection. A cellular protein targeted by all the vIRFs is ubiquitin-specific protease 7 (USP7); while replication-modulatory and latently infected PEL-cell pro-viability phenotypes of USP7 targeting have been identified for vIRFs 1-3, the significance of the interaction of vIRF-4 with USP7 has remained undetermined. Here we show, through genetic ablation of the vIRF-4-USP7 interaction in infected cells, that vIRF-4 association with USP7 is necessary for optimal expression of vIRF-4 and normal HHV-8 replication.

Direct and biologically significant interactions of human herpesvirus 8 interferon regulatory factor 1 with STAT3 and Janus kinase TYK2.

Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs) that target cellular IRFs and/or other innate-immune and stress signaling regulators and suppress the cellular response to viral infection and replication. For vIRF-1, cellular protein targets include IRFs, p53, p53-activating ATM kinase, BH3-only proteins, and antiviral signaling effectors MAVS and STING; vIRF-1 inhibits each, with demonstrated or likely promotion of HHV-8 de novo infection and productive replication. Here, we identify direct interactions of vIRF-1 with STAT3 and STAT-activating Janus kinase TYK2 (the latter reported previously by us to be inhibited by vIRF-1) and suppression by vIRF-1 of cytokine-induced STAT3 activation.

STAT and Janus kinase targeting by human herpesvirus 8 interferon regulatory factor in the suppression of type-I interferon signaling.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is involved etiologically in AIDS-associated KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease, in which both viral latent and lytic functions are important. HHV-8 encodes four viral interferon regulatory factors (vIRFs) that are believed to contribute to viral latency (in PEL cells, at least) and/or to productive replication via suppression of cellular antiviral and stress signaling. Here, we identify vIRF-1 interactions with signal transducer and activator of transcription (STAT) factors 1 and 2, interferon (IFN)-stimulated gene factor 3 (ISGF3) cofactor IRF9, and associated signal transducing Janus kinases JAK1 and TYK2.

Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis.

Mitochondria support multiple cell functions, but an accumulation of dysfunctional or excessive mitochondria is detrimental to cells. We previously demonstrated that a defect in the autophagic removal of mitochondria, termed mitophagy, leads to the acceleration of apoptosis induced by herpesvirus productive infection. However, the exact molecular mechanisms underlying activation of mitophagy and regulation of apoptosis remain poorly understood despite the identification of various mitophagy-associated proteins.

Novel Functions and Virus-Host Interactions Implicated in Pathogenesis and Replication of Human Herpesvirus 8.

Human herpesvirus 8 (HHV-8) is classified as a γ2-herpesvirus and is related to Epstein-Barr virus (EBV), a γ1-herpesvirus. One important aspect of the γ-herpesviruses is their association with neoplasia, either naturally or in animal model systems. HHV-8 is associated with B-cell-derived primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), endothelial-derived Kaposi's sarcoma (KS), and KSHV inflammatory cytokine syndrome (KICS).

Kaposi's Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). The cellular transcription factor (TF) interferon (IFN) regulatory factor 4 (IRF4) is an essential oncogene in PEL, but its specific role in PEL and how KSHV deregulates IRF4 remain unknown. Here, we report that the KSHV latency protein viral interferon regulatory factor 3 (vIRF3) cooperates with IRF4 and cellular BATF (basic leucine zipper ATF-like TF) to drive a super-enhancer (SE)-mediated oncogenic transcriptional program in PEL.

Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication.

Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) is a cytokine that is poorly secreted and localized largely to the endoplasmic reticulum (ER). It has been implicated, along with other HHV-8 proinflammatory and/or angiogenic viral proteins, in HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), in addition to an MCD-related disorder involving systemic elevation of proinflammatory cytokines, including vIL-6 and human IL-6 (hIL-6). In these diseases, lytic (productive) replication, in addition to viral latency, is believed to play a critical role.

USP7-Dependent Regulation of TRAF Activation and Signaling by a Viral Interferon Regulatory Factor Homologue.

Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs 1 to 4), all of which are expressed during lytic replication and inhibit a variety of antiviral signaling pathways. Viral IRFs 1, 2, and 3 are also expressed during latency in primary effusion lymphoma (PEL) cells, and vIRF-1 and vIRF-3 have been reported to promote PEL cell viability. Viral IRFs 1, 3, and 4 are known to interact with ubiquitin-specific protease 7 (USP7); interactions of vIRF-1 and vIRF-3 with USP7 promote PEL cell viability and regulate productive replication.

Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus.

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies.

Near doubling of Brazil's intensive row crop area since 2000.

Brazil has become a global leader in the production of commodity row crops such as soybean, sugarcane, cotton, and corn. Here, we report an increase in Brazilian cropland extent from 26.0 Mha in 2000 to 46.

Insulin-Like Growth Factor 2 Receptor Expression Is Promoted by Human Herpesvirus 8-Encoded Interleukin-6 and Contributes to Viral Latency and Productive Replication.

Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) localizes largely to the endoplasmic reticulum (ER) and here associates functionally with both the gp130 signal transducer and the novel ER membrane protein vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2). The latter interaction contributes to the viability of latently infected primary effusion lymphoma (PEL) cells and to HHV-8 productive replication, in part via promotion of ER-associated degradation (ERAD) of nascent pro-cathepsin D (pCatD) and consequent suppression of lysosome-localized proapoptotic mature CatD. Here we report that VKORC1v2 associates with insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, which is involved in trafficking of mannose-6-phosphate-conjugated glycoproteins to lysosomes.

Human Herpesvirus 8 Interleukin-6 Interacts with Calnexin Cycle Components and Promotes Protein Folding.

Viral interleukin-6 (vIL-6) encoded by human herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase and signal transducer and activator of transcription signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2).

Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease.

The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures.

Functional Segregation within the Muscles of Aquatic Propulsion in the Asiatic Water Monitor (Varanus salvator).

Water monitor lizards (Varanus salvator) swim using sinusoidal oscillations generated at the base of their long (50% of total body length) tail. In an effort to determine which level of the structural/organizational hierarchy of muscle is associated with functional segregation between the muscles of the tail base, an array of muscle features-myosin heavy chain profiles, enzymatic fiber types, twitch and tetanic force production, rates of fatigue, muscle compliance, and electrical activity patterns-were quantitated. The two examined axial muscles, longissimus, and iliocaudalis, were generally similar at the molecular, biochemical, and physiological levels, but differed at the biomechanics level and in their activation pattern.

Psychotherapy and Its Role in Psychiatric Practice: A Position Paper. II. Objective, Subjective, and Intersubjective Science.

In the first article in this 2-part series, we outlined a psychobiological model of psychiatric treatment and reviewed the evidence showing psychotherapy to be a form of biological intervention that induces lasting alterations in brain structure and function. In this second article, we focus on the adaptive model of psychopathology, the effectiveness of psychotherapeutic interventions, the synergistic effects of combined psychotherapy and psychopharmacology treatments, and attention to the patient's subjective experience and the doctor-patient alliance to complement an "objective" case formulation. The evidence strongly suggests the need for an integrated treatment approach based on the objective, subjective, and intersubjective science that forms the foundation of psychiatry as a clinical discipline, in which psychotherapy and psychopharmacology are seen as complementary treatments within a systemic approach to psychiatric care and training.

Psychotherapy and its Role in Psychiatric Practice: A Position Paper. I. Psychiatry as a Psychobiological Discipline.

Economic, political, and ideological landscapes have impacted the practice of psychiatry throughout its evolution as a medical discipline. Despite enormous scientific advances over the course of the past century, many psychiatrists continue to operate with a split Cartesian picture of mind versus brain and entrenched ideological positions ranging from biological "chemical imbalance" to rigidly followed manualized psychotherapy approaches, both of which frequently result in fractured clinical care. With the impact of systemic economic and political pressures in Canada and the United States, the attention to the doctor-patient relationship has taken a back seat to high-volume practices, computerized assessment tools, and the focus on evidence-based treatments for behaviorally defined syndromes in the Diagnostic and Statistical Manual of Mental Disorders that often come at the expense of the patient's experience of his or her illness.

Promotion of Endoplasmic Reticulum-Associated Degradation of Procathepsin D by Human Herpesvirus 8-Encoded Viral Interleukin-6.

Unlabelled: The interleukin-6 homologue (viral interleukin-6 [vIL-6]) of human herpesvirus 8 is implicated in viral pathogenesis due to its proproliferative, inflammatory, and angiogenic properties, effected through gp130 receptor signaling. In primary effusion lymphoma (PEL) cells, vIL-6 is expressed latently and is essential for normal cell growth and viability. This is mediated partly via suppression of proapoptotic cathepsin D (CatD) via cocomplexing of the endoplasmic reticulum (ER)-localized CatD precursor, pro-CatD (pCatD), and vIL-6 with the previously uncharacterized ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2).

Human herpesvirus 8 viral interleukin-6 signaling through gp130 promotes virus replication in primary effusion lymphoma and endothelial cells.

The contributions of human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) to virus biology remain unclear. Here we examined the role of vIL-6/gp130 signaling in HHV-8 productive replication in primary effusion lymphoma and endothelial cells. Depletion and depletion-complementation experiments revealed that endoplasmic reticulum-localized vIL-6 activity via gp130 and gp130-activated signal transducer and activator of transcription (STAT) signaling, but not extracellular signal-regulated kinase (ERK) activation, was critical for vIL-6 proreplication activity.

Human herpesvirus 8 interleukin-6 contributes to primary effusion lymphoma cell viability via suppression of proapoptotic cathepsin D, a cointeraction partner of vitamin K epoxide reductase complex subunit 1 variant 2.

Human herpesvirus 8 (HHV-8) interleukin-6 (vIL-6) promotes cell proliferation and survival and is proangiogenic, implicating it as a contributor to virus-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Although predominantly lytically expressed, vIL-6 is also produced at low, functional levels during latency in PEL cells. Unlike other IL-6 cytokines, vIL-6 is secreted very inefficiently and localizes in the endoplasmic reticulum (ER).

Molecular biology of human herpesvirus 8: novel functions and virus-host interactions implicated in viral pathogenesis and replication.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the second identified human gammaherpesvirus. Like its relative Epstein-Barr virus, HHV-8 is linked to B-cell tumors, specifically primary effusion lymphoma and multicentric Castleman's disease, in addition to endothelial-derived KS. HHV-8 is unusual in its possession of a plethora of "accessory" genes and encoded proteins in addition to the core, conserved herpesvirus and gammaherpesvirus genes that are necessary for basic biological functions of these viruses.

Role of human herpesvirus 8 interleukin-6-activated gp130 signal transducer in primary effusion lymphoma cell growth and viability.

Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. HHV-8-encoded viral interleukin-6 (vIL-6) is believed to contribute to pathogenesis via proproliferative, antiapoptotic, and proangiogenic activities. In PEL cells, vIL-6 is produced in functional amounts during viral latency and promotes the growth of these cells, mediating its activity from the endoplasmic reticulum (ER), where it is predominantly localized.