Special Issue "Immune Evasion"

Guest Editor
Prof. Dr. Annette Oxenius
ETH Zürich, Institute of Microbiology HCI G, 401 Wolfgang-Pauli-Str. 10, 8093 Zuerich, Switzerland
Website: http://www.micro.biol.ethz.ch/people/aoxenius/index
E-Mail: aoxenius@micro.biol.ethz.ch
Phone: +41 44 632 33 17

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Type of Paper: Article
Title: Immune Evasion Strategies of Ranaviruses and Innate Immune Responses to these Emerging Pathogens
Authors: Leon Grayfer¹, Guangchun Chen¹, Gregory V Chinchar² and Jacques Robert^1,*
Affiliations: ¹ Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
² Department of Microbiology, University of Mississippi Medical Center, Jackson, MS
^* Author to whom correspondence should be addressed; E Mail: Jacques_Robert@urmc.rochester.edu; Tel.: +1-585-275-1722; Fax +1-585- 473-9573.
Abstract: Ranaviruses (RV, Iridoviridae) are large double-stranded DNA viruses that infect fish, amphibians and reptiles.  For ecological and commercial reasons, considerable attention has been drawn to the increasing prevalence of ranaviral infections in wild populations and under aquacultural setting.  Importantly, RVs appear to be capable of crossing species barriers of numerous poikilotherms, suggesting that these pathogens possess potent immune evasion mechanisms.  Indeed, while some of the ranaviral 95-100 predicted genes encode putative evasion proteins (e.g., vIFa, vCARD), roughly two-thirds of these genes do not share significant sequence identity with known viral or eukaryotic genes.  Accordingly, the investigation of ranaviral virulence and immune evasion strategies is promising for elucidating potential antiviral targets. In this regard, recombination-based technology is being employed to knock out gene candidates in the best-characterized RV member, Frog Virus (FV3).  Concurrently, by using animal infection models with extensively characterized immune systems, such as the African clawed frog, Xenopus laevis, it is becoming evident that components of innate immunity are at the forefront of virus-host interactions.  For example, cells of the macrophage lineage represent important combatants of RV infections while themselves serving as targets for viral infection, maintenance and possibly dissemination.  This review focuses on the recent advances in the understanding of the RV immune evasion strategies with emphasis on the roles of the innate immune system in ranaviral infections.
Keywords: Iridovirus, ranavirus, FV3, frog virus 3, innate immunity, macrophage, anti-viral, immune-evasion, cytokines, inflammation
Abbreviations: ATV: Ambystoma tiginum virus; BIV: Bohle Iridovirus; CARD: caspase activation and recruitment domain; CCV: channel catfish herpes virus; DE: delayed early genes; EHNV: epizootic haematopoietic necrosis virus; eIF2a: eukaryotic initiation factor 2 alpha; FV3: frog virus 3; HIV: human immunodeficiency virus; IE: immediate early genes; IFNg: interferon gamma; IL-1b: interleukin-1 beta; IRF: interferon regulatory factor; L: late genes; MAPK: mitogen activated protein kinase; MX1: Myxovirus-resistance1; ORF: open reading frame; PKR: RNA-dependent protein kinase; PL: peritoneal leukocyte; RCV-Z: Rana catesteiana Virus Z; RV: ranavirus; SGIV: Singapore Grouper Iridovirus; TGIV: Taiwan Grouper Iridovirus; TNFa: tumor necrosis factor alpha; vIFa: viral initiation factor-alpha

Type of Paper: Review
Title: Herpesvirus Exploitation of Host Immune Inhibitory Pathways
Authors: Gabrielle Stack and Ian R. Humphreys
Affiliation: Institute of Infection and Immunity, Cardiff University, UK
Abstract: Numerous approaches are employed by herpesviruses to avoid clearance by the host immune response, enabling acute infection, persistence and dissemination. A key feature of mammalian immune systems is regulatory pathways that limit immune responsiveness. The primary functions of these mechanisms are to control autoimmunity and limit exuberant responses to harmless antigen in mucosal surfaces. However, such pathways can be exploited by viral pathogens. Herein, we will outline current understanding of the functional outcomes of immune inhibitory signals during herpesviruses infection in vivo. Furthermore, we will discuss potential manipulation of these pathways by pathogenic human herpesviruses.

Type of Paper: Article
Title: T Cell Memory in the Context of Persistent Herpes Viral Infections
Author: Prof. Dr. Annette Oxenius
Affiliation: ETH Zürich, Institut f. Mikrobiologie, HCI G 401, Wolfgang-Pauli-str. 10, 8093 Zuerich, Switzerland; E-Mail: aoxenius@micro.biol.ethz.ch
Abstract: The generation of a functional memory T cell pool upon primary encounter with an infectious pathogen is, in combination with humoral immunity, an essential process to confer protective immunity against reencounters with the same pathogen. A prerequisite for the generation and maintenance of long-lived memory T cells is the absence of antigen, which is fulfilled upon resolution of acute viral infections. Memory T cells play also a fundamental role during persistent viral infections by contributing to relative control and immuosurveillance of active replication or viral reactivation, respectively. However, the dynamics, the phenotype, the mechanisms of maintenance and the functionality of memory T cells which develop upon acute / resolved infection as opposed to chronic / latent infection differ substantially. In this review we summarize current knowledge about memory CD8 T cell responses elicited during a-, b-, and g-herpes viral infections with major emphasis on the induction, maintenance and function of virus-specific memory CD8 T cells during viral latency and we discuss how the peculiar features of these memory CD8 T cell responses might be beneficial for the development of T cell based vaccine strategies.

Type of Paper: Article
Title: Evasion of Influenza A Viruses from Innate and Adaptive Immune Responses
Author: Prof. Dr. G. F. Rimmelzwaan
Affiliation: Department of Virology, Room Ee17-26, Erasmus MC – faculty, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands; E-Mail: g.rimmelzwaan@erasmusmc.nl
Abstract: In the present review we discuss various immune evasion strategies used by influenza A viruses to avoid interference by host immune responses with their replication. The first line of host defense that the virus needs to overcome in order to infect and reproduce in (human) host cells, is the innate immune response. After the virus has established an infection, adaptive immune responses are activated. These responses consist of a humoral arm, in the form of virus-specific antibodies produced by B cells, and a cellular arm, in the form of virus-specific cytotoxic T cells (CTLs). The continuous accumulation of mutations (antigenic drift) in the envelope proteins (HA and NA) as well as the more drastic reassortment of the viral genome (antigenic shift) allows the virus to escape from recognition by (virus neutralizing) antibodies. Therefore, the current influenza vaccines, which aim at inducing antibody responses, are unable to afford lifelong protection and need to be updated almost annually. Although the internal viral proteins are more conserved, the virus has developed various strategies to avoid recognition by CTLs directed to these proteins. Since T cell recognition has our main interest, we will mainly focus on evasion of influenza viruses from the cellular immune response.

Type of Paper: Review
Title: What have we Learnt About the Immune Evasion Strategies of the Hepatitis C Virus from Studies on a Cohort of Irish Women Infected Iatrogenically?
Authors: Elizabeth J. Ryan¹, Nigel J. Stevenson² and Cliona O’Farrelly^2,3
Affiliation: ¹ Centre for Colorectal Disease, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland; E-Mail: elizabeth.ryan.1@ucdconnect.ie
² School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland; E-Mail: n.stevenson@tcd.ie
³ School of Medicine, Trinity College Dublin, Dublin 2, Ireland; E-Mail: cliona.ofarrelly@tcd.ie
Abstract: Hepatitis C virus (HCV) infection can persist in the liver for many decades, often causing very little damage. It is still not clear why certain individuals have such a benign disease course, while in others infection results in liver cirrhosis or hepatocellular carcinoma. Unravelling this conundrum is complicated by the fact that the different genotypes of HCV have different natural histories, the virus has a high mutation rate and any given individual is infected with many quasi-species. Added to this is the complexity of studying viral infection in cohorts of patients infected with different viral strains at different times via different routes of infection, who may have other co-morbidities or viral infections such as HIV or Hepatitis B.
In 1977/78 over 700 Irish women received Anti-D from batches that were contaminated with the same strain of HCV genotype 1, infection was confirmed in over 500 of these women. All the women in this cohort are Caucasian and were of childbearing age when they were infected with the same viral strain at approximately the same time. Therefore they are an ideal cohort in which to study virus –immune interactions as many of the variables that confound such studies are eliminated.
Here we will review what we have so far determined regarding how HCV evades the immune response from studies of this cohort including innate and adaptive immune cell function, host genetics and response to type I interferon.

Type of Paper: Review
Title: Manipulation of the MHC class II antigen presentation pathway by Herpesviruses
Authors: Jianmin Zuo and Martin Rowe
Affiliation: School of Cancer Sciences, University of Birmingham, UK; E-Mail: M.ROWE@bham.ac.uk; j.zuo@bham.ac.uk
Abstract: Persistent lifelong infection by herpesviruses is achieved through a balance between host immune responses and viral immune evasion.  Here, we review the importance of the contribution of CD4+ T cell responses to viral infection, and the multiple strategies evolved in the herpesviruses to evade these responses by targeting different points on the MHC-II antigen presentation pathway.  Such mechanisms include the suppression of CIITA to inhibit the synthesis of MHC-II molecules, interference with the transport of DR molecules leading to their inappropriate localisation and/or degradation, and modulation of the invariant chain chaperone of HLA-DR.