Special Issue "Modulation of Apoptosis by Viral Infection"

Guest Editor
Prof. Dr. John A. Blaho
Professor of Microbiology, Mount Sinai School of Medicine, Annenberg Building Room 16-23, 1468 Madison Avenue, New York, NY 10029, USA
Website: http://www.mssm.edu/profiles/john-a-blaho
E-Mail: John.Blaho@mssm.edu
Phone: 212-241-7318
Fax: 212-534-1684
Interests: Molecular Virology; Regulation of Herpes Simplex Virus Replication; Apoptosis and Signal Transduction; Biotechnology; Oncoapoptosis for Cancer Therapy

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed Open Access monthly journal published by MDPI.

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Type of Paper: Review
Title: Contributions of Epstein-Barr Nuclear Antigen 1 (EBNA1) to Cell Immortalization and Survival
Author: Lori Frappier
Affiliation: Department of Molecular Genetics, University of Toronto
Abstract: Epstein-Barr virus (EBV) immortalizes host cells as part of its latent mode of infection.  As a result of this ability to promote cell proliferation and survival, EBV infection contributes to the development of several kinds of B-cell lymphomas and epithelial tumours. The EBV EBNA1 protein is the only EBV protein expressed in all EBV-associated tumours and plays multiple important roles in EBV latency.  In addition to its well-studied roles in viral DNA replication, segregation and transcriptional activation, several studies have identified roles of EBNA1 in manipulating cellular processes that result in reduced apoptosis and increased cell survival. This review discusses the cellular effects of EBNA1 and mechanisms by which they occur.

Type of Paper: Review
Title: The Significance and Molecular Mechanisms of Apoptosis Induced by Influenza A Virus Infection
Authors: Takuya Shiozaki and Tadaaki Miyazaki
Affiliation: Research Section of Probiotics Immunology, Institute for Genetic Medicine, Hokkaido University, Japan; E-mail: miyazaki@czc.hokudai.ac.jp
Abstract: Influenza is an infectious respiratory disease caused by influenza virus infection. Apoptosis induction in host cells is closely related to the pathophysiology of influenza. Aberrant production of inflammatory cytokines, the so-called ‘cytokine storm’, occurring in organs infected with influenza A virus, causes multi-organ disorders through apoptosis induction.
Inflammatory cytokines belonging to TNF ligand superfamily, such as TNF-α, FasL and TRAIL, have a critical role for induction of the ‘cytokine storm’. These ligands activate the caspase-dependent signalling pathway for apoptosis induction.
On the other hand, these signals are also involved in the replication of influenza A virus. Expression levels of FasL and TRAIL are increased by this viral infection and the stimulation of these receptors is required for the effective viral replication. Therefore, identification of the molecules, important for these signals is necessary to provide effective treatment and prevent lethal infections against influenza. In this review, we discuss the significance and role of signaling molecules, such as FasL, TRAIL, Siva-1 and caspases to regulate apoptosis induction in host cells after the infection with influenza A virus.

Type of Paper: Review
Title: Modulation of apoptosis by the Hepatitis B Virus
Authors: Michael J. Bouchard and Siddharta Rawat
Affiliation: Dept. of Biochemistry and Molecular Biology, Director, Graduate Program in Molecular and Cellular Biology and Genetics, Drexel University College of Medicine, 245 N. 15th St. NCB 11312, Philadelphia, PA 19102, (215) 762-1898 office, (215) 762-4452 fax; E-mails: michael.bouchard@drexelmed.edu, rawat.sid@gmail.com
Abstract: Worldwide, an estimated 350 million people are chronically infected with the Hepatitis B Virus (HBV); chronic infection with HBV is associated with the development of severe liver diseases including hepatitis and cirrhosis. Individuals who are chronically infected with HBV also have a significantly higher risk of developing hepatocellular carcinoma (HCC) than uninfected individuals. The HBV X protein (HBx) is a key regulatory HBV protein that is important for HBV replication and is thought to play a crucial role in the development of HCC in chronically HBV-infected individuals. Although some of the functions of HBx that may contribute to the development of HCC have been characterized, many HBx functions, and their putative roles during the development of HBV-associated HCC, remain undefined. HBx is a multifunctional protein that localizes to the cytoplasm, nucleus, and mitochondria of HBV-infected hepatocytes. HBx regulates numerous cellular signal transduction pathways and transcription factors as well as cell cycle progression and apoptosis. In this review, we will summarize reports that have characterized the impact of HBx expression on cellular apoptotic pathways. Although various effects of HBx on apoptotic pathways have been observed in different model systems, recent studies of HBx activities in biologically relevant hepatocyte models systems have begun to clarify apoptotic effects of HBx and suggest mechanisms that could link HBx modulation of apoptotic pathways to the development of HBV-associated HCC.

Type of Paper: Review
Title: Alpha-herpesvirinae subfamily members express products in latently infected sensory neurons that promote survival of infected neurons.
Author: Clinton Jones
Affiliation: School of Veterinary Medicine and Biomedical Sciences, The Nebraska Center for Virology, University of Nebraska, Lincoln, Fair Street at East Campus Loop, Lincoln, NE, 68583-0905, Phone: (402) 472-1890, FAX: (402) 472-9690, E-mail: cjones@unlnotes.unl.edu
Key Words: Herpes simplex virus type 1 (HSV-1), Bovine herpesvirus 1 (BHV-1), latency, sensory neurons, latency-associated transcript, apoptosis regulation.
Abstract: Members of the alpha-herpesvirinae subfamily, herpes simplex virus type 1 (HSV-1) and bovine herpesvirus 1 (BHV-1), establish life-long latency in sensory neurons. If acute infection is initiated in mucosal surfaces that line the oral, ocular, or nasal cavity, the primary site of latency is sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. During productive infection, all viral gene products are expressed and infectious virus are produced. In contrast, only the latency-associated transcript (LAT; HSV-1) or latency related (LR) gene products (BHV-1) are abundantly expressed in latently infected neurons. LAT expression is important for the latency-reactivation cycle in animal models, in part, because it inhibits apoptosis, viral gene expression, and productive infection. Two small non-coding RNAs encoded by LAT interfere with apoptosis and reduce expression of ICP4, a viral gene that stimulates lytic cycle gene expression and productive infection. LR gene products enhance the establishment and maintenance of latency by inhibiting apoptosis and reducing expression of lytic cycle genes, in part by sequestering cellular transcription factors that regulate productive infection. A protein encoded by the LR gene (ORF2) and two micro-RNAs encoded by the LR gene promote survival of infected neurons. In cattle, wt expression of LR gene products is necessary for reactivation from latency. This review includes an update of how LAT and LR gene products interfere with apoptosis and regulate the latency-reactivation cycle.

Type of Paper: Review
Title: HIV-1 Induced Bystander Apoptosis
Authors: Himanshu Garg* and Anjali Joshi
Affiliations: Center of Excellence for Infectious Disease, Department of Biomedical Science, Texas Tech University Health Sciences Center, El Paso, TX.
Abstract: Apoptosis of uninfected bystander cells is a key element of HIV pathogenesis and believed to be the driving force behind the selective depletion of CD4 cells leading to immunodeficiency. While several viral proteins have been implicated in this process the complex interaction between Env glycoprotein expressed on the surface of infected cells and the receptor and coreceptor expressing bystander cells is now gaining ground. HIV utilizes CD4 as the primary receptor for entry into cells; however it is the viral co-receptor usage that greatly influences CD4 decline and progression to AIDS. This phenomenon is relatively simple for X4 viruses, which arise later during the course of the disease, are considered to be highly fusogenic, and cause a rapid CD4 T cell decline.  On the contrary, R5 viruses in general have a greater transmissibility, are encountered early during the disease and have a lesser pathogenic potential than the former. The above generalization gets complicated in numerous situations where R5 viruses persist throughout the disease and are capable of causing a rigorous CD4 decline. This review will discuss the multiple factors that are reported to influence HIV induced bystander apoptosis and pathogenesis including Env glycoprotein phenotype, virus tropism, disease stage, co-receptor expression on CD4 cells, immune activation and therapies targeting the viral envelope.

Type of Paper: Review
Title: Cell Death Inhibition by Cytomegaloviruses
Authors: Patricia Fliss and Wolfram Brune
Affiliation: Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Martinistr. 52, 20251 Hamburg, Germany, Phone: +49 40 48051 351; Email: wolfram.brune@hpi.uni-hamburg.de, http://www.hpi-hamburg.de
Abstract: As intracellular parasites viruses rely on numerous host cell functions to ensure their replication. The early induction of programmed cell death (PCD) in infected cells therefore constitutes an effective antiviral mechanism to restrict viral spread in an organism. As a countermeasure, viruses have evolved numerous strategies to inhibit the induction of PCD. Especially slowly replicating viruses such as the cytomegaloviruses (CMVs) depend on sustained cell viability. To achieve this, the CMVs encode a large set of viral cell death inhibitors that target several key regulators of cell death. Both the extrinsic and intrinsic apoptosis pathways are effectively suppressed by the CMV-encoded viral inhibitor of caspase-8 activation (vICA), viral mitochondrial inhibitor of apoptosis (vMIA), and viral inhibitor of Bak oligomerization (vIBO). Moreover, a viral inhibitor of RIP-mediated signaling (vIRS) that blocks programmed necrosis has been identified in the genome of murine CMV, indicating that this form of cell death is also an important part of the antiviral host response. Here, we give an overview about the mechanisms used by CMVs to subvert cell death induction.

Type of Paper: Review
Title: Modulation of Dendritic Cell Apoptosis by Dengue Virus Infection
Authors: Martins ST ¹, Silveira GF ¹, Goldenberg S ², Duarte dos Santos CN ¹, Alves LR ^2,* and Bordignon J ^1,*
Affiliations: ¹ Laboratório de Virologia Molecular and ² Laboratório de Regulação de Expressão Gênica from Instituto Carlos Chagas, ICC/Fiocruz.
*Corresponding authors: Juliano Bordignon and Lysangela R. Alves. Instituto Carlos Chagas – ICC/Fiocruz/PR, Rua Prof Algacyr Munhoz Máder, 3775, CEP - 81350-010, Curitiba, Paraná, Brazil. Tel: +55 41 21043330; Fax: +55 41 21043267
E-mail: bordignonjuliano@gmail.com, lys.alves@gmail.com.
Abstract: Dengue viruses and other members of the flaviviridae family are known as emergent human pathogens. After the infection through the bite of Aedes aegypti female mosquitoes, cells of the hematopoietic lineage, like dendritic cells, are the first to be infected by dengue viruses. Dendritic cell (DC) is a key antigen presenting cells, sensing pathogens, processing and presenting the antigens to T lymphocytes, triggering an adaptative immune response. Infection of DC by dengue virus may induce apoptosis, impairing its ability to present antigens to T cells contributing to dengue pathogenesis. Therefore this review will focus on mechanisms by which dengue virus triggers dendritic cell apoptosis influencing dengue disease severity.