scholarly journals Conservation of Genetically-Embedded Virus Assembly Instructions: A Novel Route to Antiviral Therapy

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 87
Author(s):  
Reidun Twarock ◽  
Peter G. Stockley ◽  
Richard J. Bingham ◽  
Eric C. Dykeman ◽  
Pierre-Philippe Dechant
Keyword(s):  
Viral Infections ◽  
Core Protein ◽  
Virus Assembly ◽  
Viral Evolution ◽  
Wild Type Virus ◽  
Viral Pathogens ◽  
Defective Interfering Particles ◽  
Novel Approach ◽  
Assembly Instructions ◽  
Genetic Message

Many single-stranded RNA viruses, including major viral pathogens, present RNA-encoded virus assembly instructions (VAIs) within their genetic message that can be isolated from the genetic code and repurposed for the design of virus-like particles. These VAIs rely on multiple dispersed RNA secondary structure elements with a consensus recognition motif for the capsid (core) protein, called packaging signals (PSs), which collectively promote capsid assembly. In this talk, I will provide evidence for the evolutionary conservation of the PS-encoded assembly instructions among different viruses in a viral family and discuss the implications of this discovery for viral evolution. I will then demonstrate how the VAIs can be exploited for therapy. In particular, defective interfering particles occur spontaneously in viral evolution as mutant strains lacking essential parts of the viral genome. Their ability to replicate in the presence of wild-type virus at the expense of virally produced resources can be mimicked by therapeutic interfering particles (TIPs). I will introduce a novel approach to the design of such TIPs based on synthetic nucleic acid sequences containing the VAIs but otherwise lacking genetic information. Using multiscale models of a viral infection, I will demonstrate the potential of these particles in both the prophylaxis and treatment of RNA viral infections.

scholarly journals Therapeutic interfering particles exploiting viral replication and assembly mechanisms show promising performance: a modelling study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Farzad Fatehi ◽  
Richard J. Bingham ◽  
Pierre-Philippe Dechant ◽  
Peter G. Stockley ◽  
Reidun Twarock
Keyword(s):  
Viral Infections ◽  
Virus Assembly ◽  
Rna Packaging ◽  
Packaging Signal ◽  
Protein Coding ◽  
Defective Interfering Particles ◽  
Viral Genomes ◽  
Viral Particles ◽  
Promising Treatment ◽  
Key Aspects

AbstractDefective interfering particles arise spontaneously during a viral infection as mutants lacking essential parts of the viral genome. Their ability to replicate in the presence of the wild-type (WT) virus (at the expense of viable viral particles) is mimicked and exploited by therapeutic interfering particles. We propose a strategy for the design of therapeutic interfering RNAs (tiRNAs) against positive-sense single-stranded RNA viruses that assemble via packaging signal-mediated assembly. These tiRNAs contain both an optimised version of the virus assembly manual that is encoded by multiple dispersed RNA packaging signals and a replication signal for viral polymerase, but lack any protein coding information. We use an intracellular model for hepatitis C viral (HCV) infection that captures key aspects of the competition dynamics between tiRNAs and viral genomes for virally produced capsid protein and polymerase. We show that only a small increase in the assembly and replication efficiency of the tiRNAs compared with WT virus is required in order to achieve a treatment efficacy greater than 99%. This demonstrates that the proposed tiRNA design could be a promising treatment option for RNA viral infections.

The Diagnosis of Viral Disease by Electron Microscopy

1982 ◽  
Vol 40 ◽  
pp. 270-273
Author(s):  
William B. McCombs ◽  
Cameron E. McCoy
Keyword(s):  
Electron Microscopy ◽  
Hospital Stay ◽  
Viral Infections ◽  
Medical Profession ◽  
Bacterial Pathogens ◽  
Viral Disease ◽  
Viral Pathogens ◽  
Academic Interest ◽  
The Past

Recent years have brought a reversal in the attitude of the medical profession toward the diagnosis of viral infections. Identification of bacterial pathogens was formerly thought to be faster than identification of viral pathogens. Viral identification was dismissed as being of academic interest or for confirming the presence of an epidemic, because the patient would recover or die before this could be accomplished. In the past 10 years, the goal of virologists has been to present the clinician with a viral identification in a matter of hours. This fast diagnosis has the potential for shortening the patient's hospital stay and preventing the administering of toxic and/or expensive antibiotics of no benefit to the patient.

Endogenous Retroviruses Drive Resistance and Promotion of Exogenous Retroviral Homologs

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Elliott S. Chiu ◽  
Sue VandeWoude
Keyword(s):  
Immune Modulation ◽  
Viral Infections ◽  
Viral Evolution ◽  
Endogenous Retroviruses ◽  
Annual Review ◽  
Publication Date ◽  
Biological Functions ◽  
Self Tolerance ◽  
Vertebrate Hosts ◽  
Insight Into

Endogenous retroviruses (ERVs) serve as markers of ancient viral infections and provide invaluable insight into host and viral evolution. ERVs have been exapted to assist in performing basic biological functions, including placentation, immune modulation, and oncogenesis. A subset of ERVs share high nucleotide similarity to circulating horizontally transmitted exogenous retrovirus (XRV) progenitors. In these cases, ERV–XRV interactions have been documented and include ( a) recombination to result in ERV–XRV chimeras, ( b) ERV induction of immune self-tolerance to XRV antigens, ( c) ERV antigen interference with XRV receptor binding, and ( d) interactions resulting in both enhancement and restriction of XRV infections. Whereas the mechanisms governing recombination and immune self-tolerance have been partially determined, enhancement and restriction of XRV infection are virus specific and only partially understood. This review summarizes interactions between six unique ERV–XRV pairs, highlighting important ERV biological functions and potential evolutionary histories in vertebrate hosts. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 9 is February 16, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response

2019 ◽  
Vol 93 (22) ◽  
Author(s):  
Stefan T. Peterson ◽  
Elizabeth A. Kennedy ◽  
Pamela H. Brigleb ◽  
Gwen M. Taylor ◽  
Kelly Urbanek ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Infections ◽  
Murine Norovirus ◽  
Viral Pathogens ◽  
Genetic Ablation ◽  
Type Iii ◽  
Mucosal Surfaces ◽  
Receptor Interactions ◽  
Type Iii Ifn ◽  
Type Iii Interferon

ABSTRACT Type III interferon (IFN), or IFN lambda (IFN-λ), is an essential component of the innate immune response to mucosal viral infections. In both the intestine and the lung, signaling via the IFN-λ receptor (IFNLR) controls clinically important viral pathogens, including influenza virus, norovirus, and rotavirus. While it is thought that IFN-λ cytokines are the exclusive ligands for signaling through IFNLR, it is not known whether genetic ablation of these cytokines phenotypically recapitulates disruption of the receptor. Here, we report the serendipitous establishment of Ifnl2−/− Ifnl3−/− mice, which lack all known functional murine IFN-λ cytokines. We demonstrate that, like Ifnlr1−/− mice lacking IFNLR signaling, these mice display defective control of murine norovirus, reovirus, and influenza virus and therefore genocopy Ifnlr1−/− mice. Thus, for regulation of viral infections at mucosal sites of both the intestine and lung, signaling via IFNLR can be fully explained by the activity of known cytokines IFN-λ2 and IFN-λ3. Our results confirm the current understanding of ligand-receptor interactions for type III IFN signaling and highlight the importance of this pathway in regulation of mucosal viral pathogens. IMPORTANCE Type III interferons are potent antiviral cytokines important for regulation of viruses that infect at mucosal surfaces. Studies using mice lacking the Ifnlr1 gene encoding the type III interferon receptor have demonstrated that signaling through this receptor is critical for protection against influenza virus, norovirus, and reovirus. Using a genetic approach to disrupt murine type III interferon cytokine genes Ifnl2 and Ifnl3, we found that mice lacking these cytokines fully recapitulate the impaired control of viruses observed in mice lacking Ifnlr1. Our results support the idea of an exclusive role for known type III interferon cytokines in signaling via IFNLR to mediate antiviral effects at mucosal surfaces. These findings emphasize the importance of type III interferons in regulation of a variety of viral pathogens and provide important genetic evidence to support our understanding of the ligand-receptor interactions in this pathway.

scholarly journals Directed attenuation to enhance vaccine immunity

2021 ◽  
Vol 17 (2) ◽  
pp. e1008602
Author(s):  
Rustom Antia ◽  
Hasan Ahmed ◽  
James J. Bull
Keyword(s):  
Immune Response ◽  
Genetic Engineering ◽  
Adaptive Immunity ◽  
Immune Evasion ◽  
Viral Infections ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Innate And Adaptive Immunity ◽  
Live Attenuated Vaccines

Many viral infections can be prevented by immunizing with live, attenuated vaccines. Early methods of attenuation were hit-and-miss, now much improved by genetic engineering. However, even current methods operate on the principle of genetic harm, reducing the virus’s ability to grow. Reduced viral growth has the undesired side-effect of reducing the host immune response below that of infection with wild-type. Might some methods of attenuation instead lead to an increased immune response? We use mathematical models of the dynamics of virus with innate and adaptive immunity to explore the tradeoff between attenuation of virus pathology and immunity. We find that modification of some virus immune-evasion pathways can indeed reduce pathology yet enhance immunity. Thus, attenuated vaccines can, in principle, be directed to be safe yet create better immunity than is elicited by the wild-type virus.

scholarly journals Improved Functionality of Exhausted Intrahepatic CXCR5+ CD8+ T Cells Contributes to Chronic Antigen Clearance Upon Immunomodulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Kingsley Gideon Kumashie ◽  
Marcin Cebula ◽  
Claudia Hagedorn ◽  
Florian Kreppel ◽  
Marina C. Pils ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Cell Formation ◽  
T Cell Response ◽  
Cellular Processes ◽  
Metabolic Functions ◽  
Cpg Oligonucleotide ◽  
Novel Approach

Chronic hepatotropic viral infections are characterized by exhausted CD8+ T cells in the presence of cognate antigen in the liver. The impairment of T cell response limits the control of chronic hepatotropic viruses. Immune-modulatory strategies are attractive options to re-invigorate exhausted T cells. However, in hepatotropic viral infections, the knowledge about immune-modulatory effects on the in-situ regulation of exhausted intrahepatic CD8+ T cells is limited. In this study, we elucidated the functional heterogeneity in the pool of exhausted CD8+ T cells in the liver of mice expressing the model antigen Ova in a fraction of hepatocytes. We found a subpopulation of intrahepatic CXCR5+ Ova-specific CD8+ T cells, which are profoundly cytotoxic, exhibiting efficient metabolic functions as well as improved memory recall and self-maintenance. The intrahepatic Ova-specific CXCR5+ CD8+ T cells are possibly tissue resident cells, which may rely largely on OXPHOS and glycolysis to fuel their cellular processes. Importantly, host conditioning with CpG oligonucleotide reinvigorates and promotes exhausted T cell expansion, facilitating complete antigen eradication. The CpG oligonucleotide-mediated reinvigoration may support resident memory T cell formation and the maintenance of CXCR5+ Ova-specific CD8+ T cells in the liver. These findings suggest that CpG oligodinucleotide may preferentially target CXCR5+ CD8+ T cells for expansion to facilitate the revival of exhausted T cells. Thus, therapeutic strategies aiming to expand CXCR5+ CD8+ T cells might provide a novel approach against chronic liver infection.

Aids-Associated Viral Infections

1999 ◽  
Vol 5 (S2) ◽  
pp. 1098-1099
Author(s):  
Sara E. Miller
Keyword(s):  
Electron Microscopy ◽  
Human Immunodeficiency Virus ◽  
Viral Infections ◽  
Immune Defense ◽  
Detection Methods ◽  
Aids Patients ◽  
Viral Pathogens ◽  
Thin Sectioning ◽  
Immunodeficiency Virus ◽  
Life Threatening

Infection with human immunodeficiency virus (HIV) eventually causes a profound decrease in the body's ability to eradicate or control infections with microorganisms, including viruses. Some infections in AIDS patients are due to common organisms which are of little significance in immunocompetent individuals. Other organisms can be harbored continuously, occasionally causing disease, but normally being suppressed after a heightened immune defense; in AIDS patients, these infections can be life-threatening. Further, practices that predispose to HIV infection also permit entry of other organisms, such as hepatitis and herpesviruses. Electron microscopy is beneficial as an adjunct to other modalities for viral detection. Methods for identifying viruses, both in fluids by negative staining and in tissues by thin sectioning, have been published. Some viral pathogens, including HIV itself, are best documented by other means.HIV has been demonstrated by EM in infected individuals, but because it destroys and makes scarce the cells for which it has an affinity, it is difficult to find them.

scholarly journals Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

2014 ◽  
Vol 2014 ◽  
pp. 1-24 ◽  
Author(s):  
P. J. Klasse
Keyword(s):  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Viral Proteins ◽  
Virus Neutralization ◽  
Virus Infectivity ◽  
Viral Pathogens ◽  
Enveloped Viruses ◽  
Vaccine Candidates ◽  
Hiv 1

Neutralizing antibodies (NAbs) can be both sufficient and necessary for protection against viral infections, although they sometimes act in concert with cellular immunity. Successful vaccines against viruses induce NAbs but vaccine candidates against some major viral pathogens, including HIV-1, have failed to induce potent and effective such responses. Theories of how antibodies neutralize virus infectivity have been formulated and experimentally tested since the 1930s; and controversies about the mechanistic and quantitative bases for neutralization have continually arisen. Soluble versions of native oligomeric viral proteins that mimic the functional targets of neutralizing antibodies now allow the measurement of the relevant affinities of NAbs. Thereby the neutralizing occupancies on virions can be estimated and related to the potency of the NAbs. Furthermore, the kinetics and stoichiometry of NAb binding can be compared with neutralizing efficacy. Recently, the fundamental discovery that the intracellular factor TRIM21 determines the degree of neutralization of adenovirus has provided new mechanistic and quantitative insights. Since TRIM21 resides in the cytoplasm, it would not affect the neutralization of enveloped viruses, but its range of activity against naked viruses will be important to uncover. These developments bring together the old problems of virus neutralization—mechanism, stoichiometry, kinetics, and efficacy—from surprising new angles.

scholarly journals Molecular methods in detection and epidemiologic studies of rabbit and hare viruses: a review

2019 ◽  
Vol 31 (4) ◽  
pp. 497-508 ◽  
Author(s):  
Ewa Kwit ◽  
Artur Rzeżutka
Keyword(s):  
Virus Isolation ◽  
Epidemiologic Studies ◽  
Molecular Methods ◽  
Wild Type Virus ◽  
Wild Type ◽  
High Throughput Analysis ◽  
Viral Pathogens ◽  
Current State ◽  
Virus Strains ◽  
Generation Sequencing

Various PCR-based assays for rabbit viruses have gradually replaced traditional virologic assays, such as virus isolation, because they offer high-throughput analysis, better test sensitivity and specificity, and allow vaccine and wild-type virus strains to be fully typed and differentiated. In addition, PCR is irreplaceable in the detection of uncultivable or fastidious rabbit pathogens or those occurring in low quantity in a tested sample. We provide herein an overview of the current state of the art in the molecular detection of lagomorph viral pathogens along with details of their targeted gene or nucleic acid sequence and recommendations for their application. Apart from the nucleic acids–based methods used for identification and comprehensive typing of rabbit viruses, novel methods such as microarray, next-generation sequencing, and mass spectrometry (MALDI-TOF MS) could also be employed given that they offer greater throughput in sample screening for viral pathogens. Molecular methods should be provided with an appropriate set of controls, including an internal amplification control, to confirm the validity of the results obtained.

scholarly journals Comparison of Multiplex Gastrointestinal Pathogen Panel and Conventional Stool Testing for Evaluation of Patients With HIV Infection

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Juliana Sobczyk ◽  
Sonia Jain ◽  
Xiaoying Sun ◽  
Maile Karris ◽  
Darcy Wooten ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Retrospective Cohort ◽  
Viral Infections ◽  
Turnaround Time ◽  
Stool Culture ◽  
Chain Reaction ◽  
Viral Pathogens ◽  
Polymerase Chain Reaction Testing ◽  
Gastrointestinal Pathogen ◽  
Polymerase Chain

Abstract Background Gastrointestinal pathogen panels (GPPs) are increasingly used to identify stool pathogens, but their impact in people with HIV (PWH) is unknown. We performed a retrospective cohort study comparing GPP and conventional stool evaluation in PWH. Methods We included all PWH who underwent GPP (Biofire Diagnostics; implemented September 15, 2015) or conventional testing, including stool culture, Clostridium difficile polymerase chain reaction testing, fluorescent smears for Cryptosporidium or Giardia, and ova and parasite exams (O&P) from 2013 to 2017. A total of 1941 specimens were tested, with 169 positive specimens detected in 144 patients. We compared result turnaround time, pathogen co-infection, antibiotic treatment, and treatment outcomes between positive specimens detected by conventional testing vs GPP. Results Overall, 124 patient samples tested positive by GPP, compared with 45 patient specimens by conventional testing. The GPP group demonstrated a higher co-infection rate (48.4% vs 13.3%; P < .001) and quicker turnaround time (23.4 vs 71.4 hours; P < .001). The GPP identified 29 potential viral infections that were undetectable by conventional stool tests. Unnecessary anti-infective therapy was avoided in 9 of 11 exclusively viral infections. Exclusively nonpathogenic parasites (n = 13) were detected by conventional stool tests, the majority of which were treated with metronidazole. There were no significant differences in clinical outcomes between groups. Conclusions In PWH, GPP implementation improved antibiotic stewardship through shorter turnaround times and detection of enteric viral pathogens.

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