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Viral Strategies of Immune Evasion

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 55371

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Dr. Alessandro Sinigaglia

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Guest Editor

Department of Molecular Medicine, University of Padova, 35122 Padua, Italy
Interests: mechanisms of viral infection and immunity; development of new assays for the diagnosis of infectious diseases; microRNAs in infectious diseases

Prof. Dr. Luisa Barzon

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Guest Editor

Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
Interests: surveillance, diagnosis, and pathogenesis of emerging vector-borne viral infections; pathogenesis, diagnosis, and prevention of human papillomavirus-related diseases; investigation of virus–host interactions; development of patient-specific models of human susceptibility to viral infections; application of innovative molecular methods in infectious disease diagnosis
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Dear Colleagues,

The coordinated activation of innate and adaptive immune responses are crucial for host protection against viral diseases. However, several viruses have evolved sophisticated strategies to evade or actively suppress host immunity, which represent important components of viral pathogenesis. Mechanisms of immune evasion include, for example, escape from recognition by intracellular sensors, suppression of IFN-α/β production and signaling, subversion of immune cell function, overstimulation or suppression of inflammatory responses, modulation of autophagy and cell death mechanisms, selection of genetic variants that escape from neutralizing antibodies.

In this Special Issue, we aim for research papers and review articles that contribute to an improved understanding of the mechanisms evolved by viral pathogens to evade host innate and adaptive immunity.

Dr. Alessandro Sinigaglia
Prof. Luisa Barzon
Guest Editors

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Keywords

adaptive immune response
apoptosis
autophagy
inflammasome
inflammatory cell death
innate immune response
interferon
interferon pathway
microRNAs
natural killer cells
neutralizing antibodies
pattern recognition receptors
T cells
viral entry
viral evolution
viral proteins
viral replication

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Published Papers (11 papers)

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Research

Jump to: Review

18 pages, 25851 KiB

Open AccessArticle

Dual Role of HIV-1 Envelope Signal Peptide in Immune Evasion

by Chitra Upadhyay, Priyanka Gadam Rao and Roya Feyznezhad

Viruses 2022, 14(4), 808; https://doi.org/10.3390/v14040808 - 13 Apr 2022

Cited by 1 | Viewed by 2417

Abstract

HIV-1 Env signal peptide (SP) is an important contributor to Env functions. Env is generated from Vpu/Env encoded bicistronic mRNA such that the 5′ end of Env-N-terminus, that encodes for Env-SP overlaps with 3′ end of Vpu. Env SP displays high sequence diversity, which translates into high variability in Vpu sequence. This study aimed to understand the effect of sequence polymorphism in the Vpu-Env overlapping region (VEOR) on the functions of two vital viral proteins: Vpu and Env. We used infectious molecular clone pNL4.3-CMU06 and swapped its SP (or VEOR) with that from other HIV-1 isolates. Swapping VEOR did not affect virus production in the absence of tetherin however, presence of tetherin significantly altered the release of virus progeny. VEOR also altered Vpu’s ability to downregulate CD4 and tetherin. We next tested the effect of these swaps on Env functions. Analyzing the binding of monoclonal antibodies to membrane embedded Env revealed changes in the antigenic landscape of swapped Envs. These swaps affected the oligosaccharide composition of Env-N-glycans as shown by changes in DC-SIGN-mediated virus transmission. Our study suggests that genetic diversity in VEOR plays an important role in the differential pathogenesis and also assist in immune evasion by altering Env epitope exposure. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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10 pages, 813 KiB

Open AccessArticle

Naïve Human Macrophages Are Refractory to SARS-CoV-2 Infection and Exhibit a Modest Inflammatory Response Early in Infection

by Ziyun Zhang, Rebecca Penn, Wendy S. Barclay and Efstathios S. Giotis

Viruses 2022, 14(2), 441; https://doi.org/10.3390/v14020441 - 21 Feb 2022

Cited by 11 | Viewed by 3826

Abstract

Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN-α and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the E viral gene for SARS-CoV-2 or M gene for influenza and TCID₅₀ or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 exposed MDM with notable absence of IFN-β induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN-α enhanced proinflammatory cytokine expression upon exposure to virus. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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17 pages, 3553 KiB

Open AccessArticle

Fifty Shades of E^rns: Innate Immune Evasion by the Viral Endonucleases of All Pestivirus Species

by Elena de Martin and Matthias Schweizer

Viruses 2022, 14(2), 265; https://doi.org/10.3390/v14020265 - 27 Jan 2022

Cited by 4 | Viewed by 3191

Abstract

The genus Pestivirus, family Flaviviridae, includes four historically accepted species, i.e., bovine viral diarrhea virus (BVDV)-1 and -2, classical swine fever virus (CSFV), and border disease virus (BDV). A large number of new pestivirus species were identified in recent years. A common feature of most members is the presence of two unique proteins, N^pro and E^rns, that pestiviruses evolved to regulate the host’s innate immune response. In addition to its function as a structural envelope glycoprotein, E^rns is also released in the extracellular space, where it is endocytosed by neighboring cells. As an endoribonuclease, E^rns is able to cleave viral ss- and dsRNAs, thus preventing the stimulation of the host’s interferon (IFN) response. Here, we characterize the basic features of soluble E^rns of a large variety of classified and unassigned pestiviruses that have not yet been described. Its ability to form homodimers, its RNase activity, and the ability to inhibit dsRNA-induced IFN synthesis were investigated. Overall, we found large differences between the various E^rns proteins that cannot be predicted solely based on their primary amino acid sequences, and that might be the consequence of different virus-host co-evolution histories. This provides valuable information to delineate the structure-function relationship of pestiviral endoribonucleases. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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15 pages, 3744 KiB

Open AccessArticle

Species-Specific Inhibition of Necroptosis by HCMV UL36

by Elena Muscolino, Claudia Castiglioni, Renke Brixel, Giada Frascaroli and Wolfram Brune

Viruses 2021, 13(11), 2134; https://doi.org/10.3390/v13112134 - 22 Oct 2021

Cited by 12 | Viewed by 3285

Abstract

Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the Herpesviridae family, encode cell death inhibitors that antagonize different forms of PCD. While some viral inhibitors are broadly active in cells of different species, others have species-specific functions, probably reflecting the co-evolution of the herpesviruses with their respective hosts. Human cytomegalovirus (HCMV) protein UL36 is a dual cell death pathway inhibitor. It blocks death receptor-dependent apoptosis by inhibiting caspase-8 activation, and necroptosis by binding to the mixed lineage kinase domain-like (MLKL) protein and inducing its degradation. While UL36 has been shown to inhibit apoptosis in human and murine cells, the specificity of its necroptosis-inhibiting function has not been investigated. Here we show that UL36 interacts with both human and murine MLKL, but has a higher affinity for human MLKL. When expressed by a recombinant mouse cytomegalovirus (MCMV), UL36 caused a modest reduction of murine MLKL levels but did not inhibit necroptosis in murine cells. These data suggest that UL36 inhibits necroptosis, but not apoptosis, in a species-specific manner, similar to ICP6 of herpes simplex virus type 1 and MC159 of molluscum contagiosum virus. Species-specific necroptosis inhibition might contribute to the narrow host range of these viruses. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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17 pages, 3833 KiB

Open AccessArticle

Inhibition of MAVS Aggregation-Mediated Type-I Interferon Signaling by Foot-and-Mouth Disease Virus VP3

by Pathum Ekanayaka, Byeong-Hoon Lee, Asela Weerawardhana, Kiramage Chathuranga, Jong-Hyeon Park and Jong-Soo Lee

Viruses 2021, 13(9), 1776; https://doi.org/10.3390/v13091776 - 6 Sep 2021

Cited by 9 | Viewed by 3675

Abstract

As a structural protein of the Foot-and-mouth disease virus (FMDV), VP3 plays a vital role in virus assembly and inhibiting the interferon (IFN) signal transduction to promote FMDV replication. Previous studies demonstrated that FMDV VP3 blocks the type-I IFN response by inhibiting the mRNA expression of the mitochondrial antiviral-signaling protein (MAVS); however, the underlying mechanism is poorly understood. Here, we describe the specificity of FMDV VP3 interaction with the transmembrane (TM) domain of MAVS as FMDV driven type-I IFN inhibitory mechanism for its effective replication. The TM domain of MAVS governs the mitochondria localization of MAVS, and it is a key factor in type-I IFN signaling transduction via MAVS aggregation. Thereby, the interaction of FMDV VP3 with the TM domain of MAVS leads to the inhibition of MAVS mitochondria localization, self-association, and aggregation, resulting in the suppression of type-I IFN response. Collectively, these results provide a clear understanding of a key molecular mechanism used by the FMDV VP3 for the suppression of IFN responses via targeting MAVS. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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Review

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33 pages, 3028 KiB

Open AccessReview

The Interplay between Viruses and Host DNA Sensors

by Sandra Huérfano, Vojtech Šroller, Kateřina Bruštíková, Lenka Horníková and Jitka Forstová

Viruses 2022, 14(4), 666; https://doi.org/10.3390/v14040666 - 23 Mar 2022

Cited by 28 | Viewed by 4870

Abstract

DNA virus infections are often lifelong and can cause serious diseases in their hosts. Their recognition by the sensors of the innate immune system represents the front line of host defence. Understanding the molecular mechanisms of innate immunity responses is an important prerequisite for the design of effective antivirotics. This review focuses on the present state of knowledge surrounding the mechanisms of viral DNA genome sensing and the main induced pathways of innate immunity responses. The studies that have been performed to date indicate that herpesviruses, adenoviruses, and polyomaviruses are sensed by various DNA sensors. In non-immune cells, STING pathways have been shown to be activated by cGAS, IFI16, DDX41, or DNA-PK. The activation of TLR9 has mainly been described in pDCs and in other immune cells. Importantly, studies on herpesviruses have unveiled novel participants (BRCA1, H2B, or DNA-PK) in the IFI16 sensing pathway. Polyomavirus studies have revealed that, in addition to viral DNA, micronuclei are released into the cytosol due to genotoxic stress. Papillomaviruses, HBV, and HIV have been shown to evade DNA sensing by sophisticated intracellular trafficking, unique cell tropism, and viral or cellular protein actions that prevent or block DNA sensing. Further research is required to fully understand the interplay between viruses and DNA sensors. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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25 pages, 3892 KiB

Open AccessReview

How RSV Proteins Join Forces to Overcome the Host Innate Immune Response

by Tessa Van Royen, Iebe Rossey, Koen Sedeyn, Bert Schepens and Xavier Saelens

Viruses 2022, 14(2), 419; https://doi.org/10.3390/v14020419 - 17 Feb 2022

Cited by 20 | Viewed by 5579

Abstract

Respiratory syncytial virus (RSV) is the leading cause of severe acute lower respiratory tract infections in infants worldwide. Although several pattern recognition receptors (PRRs) can sense RSV-derived pathogen-associated molecular patterns (PAMPs), infection with RSV is typically associated with low to undetectable levels of type I interferons (IFNs). Multiple RSV proteins can hinder the host’s innate immune response. The main players are NS1 and NS2 which suppress type I IFN production and signalling in multiple ways. The recruitment of innate immune cells and the production of several cytokines are reduced by RSV G. Next, RSV N can sequester immunostimulatory proteins to inclusion bodies (IBs). N might also facilitate the assembly of a multiprotein complex that is responsible for the negative regulation of innate immune pathways. Furthermore, RSV M modulates the host’s innate immune response. The nuclear accumulation of RSV M has been linked to an impaired host gene transcription, in particular for nuclear-encoded mitochondrial proteins. In addition, RSV M might also directly target mitochondrial proteins which results in a reduced mitochondrion-mediated innate immune recognition of RSV. Lastly, RSV SH might prolong the viral replication in infected cells and influence cytokine production. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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16 pages, 2300 KiB

Open AccessReview

Host-Adapted Gene Families Involved in Murine Cytomegalovirus Immune Evasion

by Sara Becker, Annette Fink, Jürgen Podlech, Matthias J. Reddehase and Niels A. Lemmermann

Viruses 2022, 14(1), 128; https://doi.org/10.3390/v14010128 - 11 Jan 2022

Cited by 9 | Viewed by 2243

Abstract

Cytomegaloviruses (CMVs) are host species-specific and have adapted to their respective mammalian hosts during co-evolution. Host-adaptation is reflected by “private genes” that have specialized in mediating virus-host interplay and have no sequence homologs in other CMV species, although biological convergence has led to analogous protein functions. They are mostly organized in gene families evolved by gene duplications and subsequent mutations. The host immune response to infection, both the innate and the adaptive immune response, is a driver of viral evolution, resulting in the acquisition of viral immune evasion proteins encoded by private gene families. As the analysis of the medically relevant human cytomegalovirus by clinical investigation in the infected human host cannot make use of designed virus and host mutagenesis, the mouse model based on murine cytomegalovirus (mCMV) has become a versatile animal model to study basic principles of in vivo virus-host interplay. Focusing on the immune evasion of the adaptive immune response by CD8⁺ T cells, we review here what is known about proteins of two private gene families of mCMV, the m02 and the m145 families, specifically the role of m04, m06, and m152 in viral antigen presentation during acute and latent infection. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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18 pages, 3642 KiB

Open AccessReview

Structural Studies on the Shapeshifting Murine Norovirus

by Michael B. Sherman, Alexis N. Williams, Hong Q. Smith, B. Montgomery Pettitt, Christiane E. Wobus and Thomas J. Smith

Viruses 2021, 13(11), 2162; https://doi.org/10.3390/v13112162 - 26 Oct 2021

Cited by 7 | Viewed by 3481

Abstract

Noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. The calicivirus capsid is composed of 180 copies of VP1 with a molecular weight of ~58 kDa. This coat protein is divided into the N-terminus (N), the shell (S) and C-terminal protruding (P) domains. The S domain forms a shell around the viral RNA genome, while the P domains dimerize to form protrusions on the capsid surface. The P domain is subdivided into P1 and P2 subdomains, with the latter containing the binding sites for cellular receptors and neutralizing antibodies. Reviewed here are studies on murine norovirus (MNV) showing that the capsid responds to several physiologically relevant cues; bile, pH, Mg²⁺, and Ca²⁺. In the initial site of infection, the intestinal tract, high bile and metal concentrations and low pH cause two significant conformational changes: (1) the P domain contracts onto the shell domain and (2) several conformational changes within the P domain lead to enhanced receptor binding while blocking antibody neutralization. In contrast, the pH is neutral, and the concentrations of bile and metals are low in the serum. Under these conditions, the loops at the tip of the P domain are in the open conformation with the P domain floating on a linker or tether above the shell. This conformational state favors antibody binding but reduces interactions with the receptor. In this way, MNV uses metabolites and environmental cues in the intestine to optimize cellular attachment and escape antibody binding but presents a wholly different structure to the immune system in the serum. To our knowledge, this is the first example of a virus shapeshifting in this manner to escape the immune response. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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16 pages, 1728 KiB

Open AccessReview

Innate Immune Antagonism of Mosquito-Borne Flaviviruses in Humans and Mosquitoes

by Ahmed M. E. Elrefaey, Philippa Hollinghurst, Christine M. Reitmayer, Luke Alphey and Kevin Maringer

Viruses 2021, 13(11), 2116; https://doi.org/10.3390/v13112116 - 20 Oct 2021

Cited by 13 | Viewed by 5780

Abstract

Mosquito-borne viruses of the Flavivirus genus (Flaviviridae family) pose an ongoing threat to global public health. For example, dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses are transmitted by infected mosquitoes and cause severe and fatal diseases in humans. The means by which mosquito-borne flaviviruses establish persistent infection in mosquitoes and cause disease in humans are complex and depend upon a myriad of virus-host interactions, such as those of the innate immune system, which are the main focus of our review. This review also covers the different strategies utilized by mosquito-borne flaviviruses to antagonize the innate immune response in humans and mosquitoes. Given the lack of antiviral therapeutics for mosquito-borne flaviviruses, improving our understanding of these virus-immune interactions could lead to new antiviral therapies and strategies for developing refractory vectors incapable of transmitting these viruses, and can also provide insights into determinants of viral tropism that influence virus emergence into new species. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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17 pages, 4405 KiB

Open AccessReview

Immune Evasion of SARS-CoV-2 Emerging Variants: What Have We Learnt So Far?

by Ivana Lazarevic, Vera Pravica, Danijela Miljanovic and Maja Cupic

Viruses 2021, 13(7), 1192; https://doi.org/10.3390/v13071192 - 22 Jun 2021

Cited by 138 | Viewed by 14640

Abstract

Despite the slow evolutionary rate of SARS-CoV-2 relative to other RNA viruses, its massive and rapid transmission during the COVID-19 pandemic has enabled it to acquire significant genetic diversity since it first entered the human population. This led to the emergence of numerous variants, some of them recently being labeled “variants of concern” (VOC), due to their potential impact on transmission, morbidity/mortality, and the evasion of neutralization by antibodies elicited by infection, vaccination, or therapeutic application. The potential to evade neutralization is the result of diversity of the target epitopes generated by the accumulation of mutations in the spike protein. While three globally recognized VOCs (Alpha or B.1.1.7, Beta or B.1.351, and Gamma or P.1) remain sensitive to neutralization albeit at reduced levels by the sera of convalescent individuals and recipients of several anti-COVID19 vaccines, the effect of spike variability is much more evident on the neutralization capacity of monoclonal antibodies. The newly recognized VOC Delta or lineage B.1.617.2, as well as locally accepted VOCs (Epsilon or B.1.427/29-US and B1.1.7 with the E484K-UK) are indicating the necessity of close monitoring of new variants on a global level. The VOCs characteristics, their mutational patterns, and the role mutations play in immune evasion are summarized in this review. Full article

(This article belongs to the Special Issue Viral Strategies of Immune Evasion)

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