Special Issue "Arenaviruses"

Guest Editor
Prof. Dr. Stefan Kunz
Institute of Microbiology, University Hospital Center and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland
Website: http://www.unil.ch/fbm/page77326_en.html
E-Mail: Stefan.Kunz@chuv.ch
Phone: +41 21 314 77 43
Fax: +41 21 314 40 60

Dear Colleagues,

The arenaviruses are a large and diverse family of viruses that merit significant attention as powerful models for experimental virology and as important human pathogens. Over the past decades several arenaviruses have emerged as causative agents of severe viral hemorrhagic fevers that belong to the most devastating human diseases and cause considerable suffering in many countries of the Developing World. The Old World arenavirus Lassa virus is the most prevalent human pathogen among the arenaviruses with several hundred thousand infections per year in Africa with thousands of deaths. The South American hemorrhagic fever viruses Junin, Machupo, Guanarito, and Sabia have emerged as etiological agents of severe hemorrhagic fevers in Latin America. There is no licensed vaccine available and therapeutic options are restricted, resulting in 15-30% mortality in hospitalized patients. New pathogenic arenaviruses emerge with on average one new species being discovered every three years, representing a serious concern for public health.The past years have seen rapid progress in many aspects of arenavirus research. The present Special Issue covers major recent developments in molecular arenavirus virology, fundamental mechanisms of arenavirus-host cell interaction, and the development of novel anti-viral strategies against these important pathogens.

Prof. Dr. Stefan Kunz
Guest Editor

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Arenaviruses; Viral Hemorrhagic Fevers; Emerging Viruses; Virus-host Cell Interaction; Anti-viral Drugs

Type of Paper: Article
Title: Prophylaxis, Therapeutics, and Animal Modeling for Arenavirus Infections
Author: Eric Vela ^1,2
Affiliations: ¹ Battelle, 505 King Ave, Columbus, OH 43201, ² Center for Predictive Medicine, University of Louisville, 950 N. Hurstbourne Parkway, Louisville, KY 40222; E-mail: velae@battelle.org
Abstract: Arenaviruses are enveloped, bipartite negative single-stranded RNA viruses that can cause a wide spectrum of disease in humans and host animals including hemorrhagic fever.  The majority of these viruses are rodent-borne and the arenavirus family can be divided into two groups: the Lassa-Lymphocytic choriomeningitis serocomplex and the Tacaribe serocomplex.  Arenavirus-induced disease may include characteristic symptoms ranging from fever, malaise, body aches, petechiae, dehydration, hemorrhage, organ failure, shock, and in severe cases death.  Currently, there are few prophylactic and therapeutic treatments available for arenavirus-induced symptoms apart from supportive treatment and ribavirin.  Therefore, further therapeutic and prophylactic research strategies are necessary for efficacy testing in various relevant animal models.  Because of the potential for aerosol production, person-to-person spread, the ability to cause lethal or debilitating disease in humans, limited treatment options, and potential as a bio-weapon, the development of prophylactics and therapeutics is essential.  This article reviews the current prophylactic and therapeutic strategies being conducted for arenavirus infection in host animals, in addition to the relevant animal models utilized to test such treatment options.

Type of Paper: Review
Title: Advanced Vaccine Candidates for Lassa Fever
Author: Igor S. Lukashevich
Affiliation: Department of Pharmacology and Toxicology, School of Medicine, and the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Kentucky, USA. Phone: +1-502-852-8822; Fax: +1-852-5468; E-Mail: isluka01@louisville.edu
Abstract: Lassa virus (LASV) is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir,  Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF). LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever) with estimated 100,000-300,000 infections and 5,000-10,000 deaths annually in western Africa.  The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this paper is to overview the current status of pre-clinical development of the advanced vaccine candidates which have been tested in non-human primates. Major scientific, manufacturing, and regulatory challenges will be discussed as well.

Type of Paper: Review
Title: Junín Virus Pathogenesis and Virus Replication
Authors: Ashley Grant ¹, Alexey Seregin ¹ Cheng Huang ¹, Olga Kolokoltsova ¹ Allan R Brasier ² and Slobodan Paessler ¹
Affiliations: ¹ Department of Pathology, University of Texas Medical Branch, Galveston, Texas.  ² Institute for Translational Sciences, Department of Internal Medicine  and Sealy Center for Molecular Medicine, UTMB
Abstract: Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality. The virus is spread through the aerosolization of host rodent excreta and endemic to the humid pampas of Argentina. Recently, significant progress has been achieved with the development of new technologies (e.g. reverse genetics) that have expanded knowledge about the pathogenesis and viral replication of Junín virus. We will review the pathogenesis of Junín virus in various animal models and the role of innate and adaptive immunity during infection. We will highlight current research regarding the role of molecular biology of Junín virus in elucidating virus attenuation. We will also summarize current knowledge on Junin virus pathogenesis focusing on the recent development of vaccines and potential therapeutics.
Keywords: arenavirus; junin virus; pathogenesis

Type of Paper: Review
Title: Species-specific Variation of Arenaviruses
Authors: Juan Carlos Zapata and Maria Salvato
Affiliations: University of Maryland Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD 21201, USA; E-Mails: MSalvato@ihv.umaryland.edu, jczapata@ihv.umaryland.edu
Abstract: The arenaviruses include a single genus of single-stranded, two-segmented, enveloped RNA viruses that are carried by rodents and occasionally transmitted to primates.  As RNA viruses, arenaviruses lack an error-correcting polymerase, but structural constraints on the RNA are not so stringent as to prevent the acquisition of extra genomic segments within a single virion. In this review  we discuss the in vivo studies of arenavirus variation after infection or vaccination of different animal models.  Additionally we discuss some in vitro studies after exposure to selective pressures such as high dose, mutagens and antivirals. We also mention the recent emergence of newly discovered arenaviruses in the context of our observations of sequence variations that are species-specific.

Type of Paper: Article
Title: Arenavirus Budding: A Common Pathway with Mechanistic Differences
Authors: Svenja Wolff ¹, Hideki Ebihara ² and Allison Groseth ²
Affiliations: ¹ Institut für Virologie, Philipps Universität Marburg, Marburg, Germany. ² Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
Abstract: The Arenaviridae are a diverse and growing family of viruses that includes several agents responsible for important hemorrhagic fever diseases. Despite the importance of this family for public health much of their biology remains poorly understood. However, in recent years significant progress has been made in this regard, particularly relating to the formation and release of new enveloped virions, which is an essential step in the viral lifecycle. While this process is mediated chiefly by the viral matrix protein Z, recent evidence suggests that for some viruses the NP is also required to enhance the budding process. Here we highlight and compare distinct budding mechanisms of different arenaviruses, concentrating on the role of the matrix protein Z, its known late domain sequences and the involvement of cellular ESCRT pathway components. Finally we address the recently described roles of the nucleoprotein NP in the budding of Tacaribe virus as well as its contributions to ribonucleoprotein complex incorporation and discuss possible mechanisms related to these processes.
Keywords: budding; ESCRT pathway; matrix protein; nucleoprotein; late domain

Type of Paper: Review
Title: Uncovering Viral Protein-protein Interactions and their Role in Virus Life Cycle
Authors: ¹ Maria Eugenia Loureiro, ¹ Alejandra D’Antuono, ² Jesica M. Levingston Macleod, and ^1,* Nora López
Affiliations: ¹ Centro de Virología Animal (CEVAN), Instituto de Ciencia y Tecnología Dr. Cesar Milstein, Consejo Nacional de Ciencia y Tecnología (CONICET), Saladillo 2468, Buenos Aires C1440FFX, Argentina.
² Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029.
* Author to whom correspondence should be addressed; E-Mail: nlopezcevan@centromilstein.org.ar; Tel/Fax: (54-11) 4687-8735
Abstract: The Arenaviridae family includes important human pathogens that cause hemorrhagic fever. Replication and packaging of their bisegmented ssRNA genome involve both RNA recognition by viral proteins and a number of key protein-protein interactions. Viral RNA synthesis is directed by the virus-encoded RNA dependent-RNA polymerase (L protein) and requires viral RNA encapsidation by the Nucleoprotein (N). Additionally to the role that the interaction between L and N proteins may have in the replication process, the association between L and the small Z protein appears to modulate polymerase activity. Z is also a multifunctional structural component of the virions playing an essential role in viral morphogenesis. Indeed, interaction of Z protein with the Nucleoprotein is essential for genome packaging and Z homo-oligomerization may be an essential step for particle assembly and budding. Recent efforts to understand the molecular basis of Arenavirus life cycle have revealed details of some of these viral protein-protein interactions that will be reviewed in this article.

Type of Paper: Review
Title: Molecular Mechanism of Arenavirus Assembly and Budding
Authors: Shuzo Urata and Jiro Yasuda
Affiliation: Dept. of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto Nagasaki 852-8523, Japan; Tel. +81-095-819-7849, Fax +81-095-819-7851; E-Mail: shuzourata@nagasaki-u.ac.jp
Abstract: Arenavirus have a bi-segmented negative strand RNA genome, which encode four viral proteins, GP and NP by S segment and Z and L by L segment. These four viral proteins possess multiple functions to infect, replicate and release progeny viruses from an infected cell. Small RING finger protein, Z protein, has been known as a matrix (M) protein, which possesses a central role in viral assembly and budding. Although all arenaviruses encode Z protein, the amino acid sequence alignment show a huge variety among the species, especially at the C-terminus where the L (late)-domain locates. Recently, increasing numbers of publications demonstrate the interactions between viral protein and viral protein, and viral protein and host cellular protein, which facilitate transportation and assembly of viral components to the place where virus egress. In this review, we summarized our current knowledge of the arenavirus assembly and budding, comparing with other envelope viruses. We also refer to the restriction of arenavirus production by the antiviral cellular factor, Tetherin/BST-2.

Type of Paper: Review
Title: The Role of LCMV in Understanding Viral Immunology: Past, Present and Future
Authors: Xin Zhou ¹,  and Daniel L. Popkin ^2*
Affiliations: ¹ Case Western Reserve University: Departments of Dermatology, 10900 Euclid Avenue, Cleveland, OH 44106; E-Mail: zhouxin.jerry@gmail.com
² Case Western Reserve University: Departments of Dermatology/Pathology/Microbiology & Molecular Biology. 10900 Euclid Avenue, Cleveland, OH 44106.  E-Mail: daniel.popkin@case.edu
*    Author to whom correspondence should be addressed; E-Mail: daniel.popkin@case.edu; Tel.: +1-216-368-0237; Fax: +1-216-844-8993.
Abstract: Lymphocytic choriomeningitis virus (LCMV) is a common infection of rodents first identified over eighty years ago in St. Louis, MO. It is best known for its application in immunological studies. The history of LCMV closely correlates with the development of modern immunology. With the use of LCMV as a model pathogen several key concepts have emerged: MHC restriction, T cell memory, persistent infections, T cell exhaustion and the key role of immune pathology in disease. Given the phenomenal infrastructure within this field (e.g. defined immunodominant and subdominant epitopes to all T cell receptor specificities as well as the cognate tetramers for enumeration in vivo) the study of LCMV remains an active and productive platform for biological research across the globe to this day. Here we present a historical primer that highlights several breakthroughs since the discovery of LCMV.  Next, we highlight current research in the field and conclude with our predictions for future directions in the remarkable field of LCMV research.
Keywords: lymphocytic choriomeningitis virus; immunology; viral immunology; immune memory; persistent infection

Type of Paper: Review
Title: The Multifunctional Nature of Arenavirus RING Finger Proteins
Authors: Thomas Strecker * and Sarah Katharina Fehling
Affiliation: Institut für Virologie der Philipps-Universität Marburg, Hans-Meerwein-Str. 2, 35037 Marburg, Germany
* Corresponding author
Mailing address: Institut für Virologie, Hans-Meerwein-Str. 2, 35043 Marburg, Germany
Phone: +49-6421-28 66254. Fax: +49-6421-28 65182. E-mail: strecker@staff.uni-marburg.de
Abstract: Arenaviruses are a family of enveloped negative-sense RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi-segmented RNA genome encodes four polypeptides: the nucleoprotein NP and the surface glycoprotein GP on the small RNA segment and the polymerase L and the RING finger protein Z on the large RNA segment. Although being the smallest Arenavirus protein with a length of 90 to 99 amino acids and an approximate size of 11 kDa, the Z protein has multiple functions in the arenaviral life cycle including (i) interaction with host cell proteins; (ii) modulation of viral replication and transcription; (iii) interferon antagonism; and (iv) orchestration of viral assembly and budding. The purpose of this review is to summarize in particular the recent literature on Arenavirus RING finger proteins and to illuminate their known functions in the viral life cycle.

Type of Paper: Review
Title: Serological Assays Based on Recombinant Viral Proteins for the Diagnosis of Viral Hemorrhagic Fevers Caused by Arenaviruses
Authors: Shuetsu Fukushi, Hideki Tani, Tomoki Yoshikawa, Masayuki Saijo, and Shigeru Morikawa
Affiliation: Department of Virology 1, National Institute of Infectious Diseases. 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan
Tel: +81-42-561-0771; Fax: +81-42-561-2039; E-mail: fukushi@nih.go.jp
Abstract: The family Arenaviridae, genus Arenavirus, consists of two phylogenetically independent groups: Old World (OW) and New World (NW) complexes. Lassa and Lujo viruses in the OW complex and Guanarito, Junin, Machupo, Sabia, and Chapare viruses in the NW complex cause viral hemorrhagic fevers (VHF) in humans, leading serious public health concerns. These viruses are also considered as potential bioterrorism agents. Therefore, it is of great importance to detect these pathogens rapidly and specifically to minimize the risk and scale of arenavirus outbreaks. However, these arenaviruses are classified as the BSL-4 pathogens, making it difficult to develop diagnostics for these virus infections in the institutes without BSL-4 facilities. To get around the difficulties, antibody detection systems as a form of enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay were developed for these arenaviruses with using recombinant NPs (rNPs) of these viruses (Clin Vaccine Immunol 16(8):1132-1138, 2009, Clin Vaccine Immunol 14(9):1182-1189, 2007). Furthermore, antigen-detection assays were developed as follows. Novel monoclonal antibodies (mAbs) to the rNPs of Lassa and Junin viruses were generated. Sandwich antigen-capture (Ag-capture) ELISAs using these mAbs as capture antibodies were developed and confirmed to be sensitive and specific in detecting arenavirus NPs. These recombinant NP-based assays were proposed to be useful not only for etiological diagnosis of VHFs but also in seroepidemiological studies. We recently developed arenavirus neutralization assays using the vesicular stomatitis virus (VSV)-based pseudotypes bearing arenavirus recombinant glycoproteins. The scope of this article is to review recent advances in developing laboratory diagnostic assays based on the recombinant viral proteins for diagnosis of and epidemiological studies on the VHFs caused by arenaviruses.