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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 33614

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Dr. Stephen Barr

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Department of Microbiology and Immunology, Western University, London, ON, Canada
Interests: cellular restriction factors; antiviral proteins; HIV; Ebola; SARS-CoV-2; innate immunity; retroviral integration; HERC5; ISG15; viral antagonists; virus–host interactions
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Special Issue Information

Dear Colleagues,

Viruses are submicroscopic entities that can have a profound impact on many life forms. Understanding how viruses replicate and cause disease is critical for the development of novel antiviral therapeutics and control measures. Canadian researchers have contributed numerous important advancements in the development of tools and methods to better understand virus biology and the progression of virus-induced diseases, imaging of viruses in vitro and in vivo, mechanisms of viral pathogenesis, host immune responses against viruses, viral immune evasion, identification of novel antiviral agents, development of diagnostic reagents to characterize hidden reservoirs of viruses and for the early and accurate detection of viral infections, and in understanding how viruses jump the species barrier. This Special Issue highlights state-of-the-art virology research in Canada. We welcome submissions from Canadian institutions of original research articles and comprehensive reviews including—but not limited to—the above-mentioned areas.

Dr. Stephen Barr
Guest Editor

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Keywords

Canada
state-of-the-art
virus-host interactions
virus biology
progression of virus-induced diseases
imaging of viruses
viral pathogenesis
viral immune evasion
antiviral responses
antiviral agents
diagnostic reagents

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Published Papers (10 papers)

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Research

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16 pages, 1915 KiB

Open AccessArticle

microRNA-185 Inhibits SARS-CoV-2 Infection through the Modulation of the Host’s Lipid Microenvironment

by Nadine Ahmed, Magen E. Francis, Noreen Ahmed, Alyson A. Kelvin and John Paul Pezacki

Viruses 2023, 15(9), 1921; https://doi.org/10.3390/v15091921 - 14 Sep 2023

Cited by 1 | Viewed by 1917

Abstract

With the emergence of the novel betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there has been an urgent need for the development of fast-acting antivirals, particularly in dealing with different variants of concern (VOC). SARS-CoV-2, like other RNA viruses, depends on host cell machinery to propagate and misregulate metabolic pathways to its advantage. Herein, we discovered that the immunometabolic microRNA-185 (miR-185) restricts SARS-CoV-2 propagation by affecting its entry and infectivity. The antiviral effects of miR-185 were studied in SARS-CoV-2 Spike protein pseudotyped virus, surrogate virus (HCoV-229E), as well as live SARS-CoV-2 virus in Huh7, A549, and Calu-3 cells. In each model, we consistently observed microRNA-induced reduction in lipid metabolism pathways-associated genes including SREBP2, SQLE, PPARG, AGPAT3, and SCARB1. Interestingly, we also observed changes in angiotensin-converting enzyme 2 (ACE2) levels, the entry receptor for SARS-CoV-2. Taken together, these data show that miR-185 significantly restricts host metabolic and other pathways that appear to be essential to SAR-CoV-2 replication and propagation. Overall, this study highlights an important link between non-coding RNAs, immunometabolic pathways, and viral infection. miR-185 mimics alone or in combination with other antiviral therapeutics represent possible future fast-acting antiviral strategies that are likely to be broadly antiviral against multiple variants as well as different virus types of potential pandemics. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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14 pages, 2839 KiB

Open AccessArticle

Cellular Immune Responses to SARS-CoV-2 in Exposed Seronegative Individuals

by Natasha J. Norton, Kayla A. Holder, Danielle P. Ings, Debbie O. A. Harnum, Rodney S. Russell and Michael D. Grant

Viruses 2023, 15(4), 996; https://doi.org/10.3390/v15040996 - 18 Apr 2023

Cited by 5 | Viewed by 2210

Abstract

Some SARS-CoV-2-exposed individuals develop immunity without overt infection. We identified 11 individuals who were negative by nucleic acid testing during prolonged close contact and with no serological diagnosis of infection. As this could reflect natural immunity, cross-reactive immunity from previous coronavirus exposure, abortive infection due to de novo immune responses, or other factors, our objective was to characterize immunity against SARS-CoV-2 in these individuals. Blood was processed into plasma and peripheral blood mononuclear cells (PBMC) and screened for IgG, IgA, and IgM antibodies (Ab) against SARS-CoV-2 and common β-coronaviruses OC43 and HKU1. Receptor blocking activity and interferon-alpha (IFN-α) in plasma were also measured. Circulating T cells against SARS-CoV-2 were enumerated and CD4⁺ and CD8⁺ T cell responses discriminated after in vitro stimulation. Exposed uninfected individuals were seronegative against SARS-CoV-2 spike (S) and selectively reactive against OC43 nucleocapsid protein (N), suggesting common β-coronavirus exposure induced Ab cross-reactive against SARS-CoV-2 N. There was no evidence of protection from circulating angiotensin-converting enzyme (ACE2) or IFN-α. Six individuals had T cell responses against SARS-CoV-2, with four involving CD4⁺ and CD8⁺ T cells. We found no evidence of protection from SARS-CoV-2 through innate immunity or immunity induced by common β-coronaviruses. Cellular immune responses against SARS-CoV-2 were associated with time since exposure, suggesting that rapid cellular responses may contain SARS-CoV-2 infection below the thresholds required for a humoral response. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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17 pages, 3028 KiB

Open AccessArticle

The EBV Gastric Cancer Resource (EBV-GCR): A Suite of Tools for Investigating EBV-Associated Human Gastric Carcinogenesis

by Mikhail Y. Salnikov, Eric Wang, Erik Christensen, Martin A. Prusinkiewicz, Parisa Shooshtari and Joe S. Mymryk

Viruses 2023, 15(4), 853; https://doi.org/10.3390/v15040853 - 27 Mar 2023

Cited by 6 | Viewed by 3431

Abstract

Epstein-Barr virus (EBV) causes lifelong infection in over 90% of the world’s population. EBV infection leads to several types of B cell and epithelial cancers due to the viral reprogramming of host-cell growth and gene expression. EBV is associated with 10% of stomach/gastric adenocarcinomas (EBVaGCs), which have distinct molecular, pathological, and immunological characteristics compared to EBV-negative gastric adenocarcinomas (EBVnGCs). Publicly available datasets, such as The Cancer Genome Atlas (TCGA), contain comprehensive transcriptomic, genomic, and epigenomic data for thousands of primary human cancer samples, including EBVaGCs. Additionally, single-cell RNA-sequencing data are becoming available for EBVaGCs. These resources provide a unique opportunity to explore the role of EBV in human carcinogenesis, as well as differences between EBVaGCs and their EBVnGC counterparts. We have constructed a suite of web-based tools called the EBV Gastric Cancer Resource (EBV-GCR), which utilizes TCGA and single-cell RNA-seq data and can be used for research related to EBVaGCs. These web-based tools allow investigators to gain in-depth biological and clinical insights by exploring the effects of EBV on cellular gene expression, associations with patient outcomes, immune landscape features, and differential gene methylation, featuring both whole-tissue and single-cell analyses. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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17 pages, 2468 KiB

Open AccessArticle

SARS-CoV-2 Nsp2 Contributes to Inflammation by Activating NF-κB

by Émile Lacasse, Leslie Gudimard, Isabelle Dubuc, Annie Gravel, Isabelle Allaeys, Éric Boilard and Louis Flamand

Viruses 2023, 15(2), 334; https://doi.org/10.3390/v15020334 - 24 Jan 2023

Cited by 17 | Viewed by 3530

Abstract

COVID-19 is associated with robust inflammation and partially impaired antiviral responses. The modulation of inflammatory gene expression by SARS-CoV-2 is not completely understood. In this study, we characterized the inflammatory and antiviral responses mounted during SARS-CoV-2 infection. K18-hACE2 mice were infected with a Wuhan-like strain of SARS-CoV-2, and the transcriptional and translational expression interferons (IFNs), cytokines, and chemokines were analyzed in mouse lung homogenates. Our results show that the infection of mice with SARS-CoV-2 induces the expression of several pro-inflammatory CC and CXC chemokines activated through NF-κB but weakly IL1β and IL18 whose expression are more characteristic of inflammasome formation. We also observed the downregulation of several inflammasome effectors. The modulation of innate response, following expressions of non-structural protein 2 (Nsp2) and SARS-CoV-2 infection, was assessed by measuring IFNβ expression and NF-κB modulation in human pulmonary cells. A robust activation of the NF-κB p65 subunit was induced following the infection of human cells with the corresponding NF-κB-driven inflammatory signature. We identified that Nsp2 expression induced the activation of the IFNβ promoter through its NF-κB regulatory domain as well as activation of p65 subunit phosphorylation. The present studies suggest that SARS-CoV-2 skews the antiviral response in favor of an NF-κB-driven inflammatory response, a hallmark of acute COVID-19 and for which Nsp2 should be considered an important contributor. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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23 pages, 4463 KiB

Open AccessArticle

Molecular Epidemiology of HIV-1 in Ghana: Subtype Distribution, Drug Resistance and Coreceptor Usage

by Anna Appah, Charlotte J. Beelen, Don Kirkby, Winnie Dong, Aniqa Shahid, Brian Foley, Miriam Mensah, Vincent Ganu, Peter Puplampu, Linda E. Amoah, Nicholas I. Nii-Trebi, Chanson J. Brumme and Zabrina L. Brumme

Viruses 2023, 15(1), 128; https://doi.org/10.3390/v15010128 - 31 Dec 2022

Cited by 9 | Viewed by 3609

Abstract

The greatest HIV-1 genetic diversity is found in West/Central Africa due to the pandemic’s origins in this region, but this diversity remains understudied. We characterized HIV-1 subtype diversity (from both sub-genomic and full-genome viral sequences), drug resistance and coreceptor usage in 103 predominantly (90%) antiretroviral-naive individuals living with HIV-1 in Ghana. Full-genome HIV-1 subtyping confirmed the circulating recombinant form CRF02_AG as the dominant (53.9%) subtype in the region, with the complex recombinant 06_cpx (4%) present as well. Unique recombinants, most of which were mosaics containing CRF02_AG and/or 06_cpx, made up 37% of sequences, while “pure” subtypes were rare (<6%). Pretreatment resistance to at least one drug class was observed in 17% of the cohort, with NNRTI resistance being the most common (12%) and INSTI resistance being relatively rare (2%). CXCR4-using HIV-1 sequences were identified in 23% of participants. Overall, our findings advance our understanding of HIV-1 molecular epidemiology in Ghana. Extensive HIV-1 genetic diversity in the region appears to be fueling the ongoing creation of novel recombinants, the majority CRF02_AG-containing, in the region. The relatively high prevalence of pretreatment NNRTI resistance but low prevalence of INSTI resistance supports the use of INSTI-based first-line regimens in Ghana. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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16 pages, 1610 KiB

Open AccessArticle

Generation and Characterization of a SARS-CoV-2-Susceptible Mouse Model Using Adeno-Associated Virus (AAV6.2FF)-Mediated Respiratory Delivery of the Human ACE2 Gene

by Nikesh Tailor, Bryce M. Warner, Bryan D. Griffin, Kevin Tierney, Estella Moffat, Kathy Frost, Robert Vendramelli, Anders Leung, Marnie Willman, Sylvia P. Thomas, Yanlong Pei, Stephanie A. Booth, Carissa Embury-Hyatt, Sarah K. Wootton and Darwyn Kobasa

Viruses 2023, 15(1), 85; https://doi.org/10.3390/v15010085 - 28 Dec 2022

Cited by 7 | Viewed by 3063

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) that has caused a pandemic with millions of human infections. There continues to be a pressing need to develop potential therapies and vaccines to inhibit SARS-CoV-2 infection to mitigate the ongoing pandemic. Epidemiological data from the current pandemic indicates that there may be sex-dependent differences in disease outcomes. To investigate these differences, we proposed to use common small animal species that are frequently used to model disease with viruses. However, common laboratory strains of mice are not readily infected by SARS-CoV-2 because of differences in the angiotensin-converting enzyme 2 (ACE2), the cellular receptor for the virus. To overcome this limitation, we transduced common laboratory accessible strains of mice of different sexes and age groups with a novel a triple AAV6 mutant, termed AAV6.2FF, encoding either human ACE2 or luciferase via intranasal administration to promote expression in the lung and nasal turbinates. Infection of AAV-hACE2-transduced mice with SARS-CoV-2 resulted in high viral titers in the lungs and nasal turbinates, establishment of an IgM and IgG antibody response, and modulation of lung and nasal turbinate cytokine profiles. There were insignificant differences in infection characteristics between age groups and sex-related differences; however, there were significant strain-related differences between BALB/c vs. C57BL/6 mice. We show that AAV-hACE2-transduced mice are a useful for determining immune responses and for potential evaluation of SARS-CoV-2 vaccines and antiviral therapies, and this study serves as a model for the utility of this approach to rapidly develop small-animal models for emerging viruses. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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21 pages, 4643 KiB

Open AccessArticle

G-Quadruplex DNA and Other Non-Canonical B-Form DNA Motifs Influence Productive and Latent HIV-1 Integration and Reactivation Potential

by Hannah O. Ajoge, Hinissan P. Kohio, Ermela Paparisto, Macon D. Coleman, Kemen Wong, Sean K. Tom, Katie L. Bain, Charles C. Berry, Eric J. Arts and Stephen D. Barr

Viruses 2022, 14(11), 2494; https://doi.org/10.3390/v14112494 - 11 Nov 2022

Cited by 3 | Viewed by 2895

Abstract

The integration of the HIV-1 genome into the host genome is an essential step in the life cycle of the virus and it plays a critical role in the expression, long-term persistence, and reactivation of HIV expression. To better understand the local genomic environment surrounding HIV-1 proviruses, we assessed the influence of non-canonical B-form DNA (non-B DNA) on the HIV-1 integration site selection. We showed that productively and latently infected cells exhibit different integration site biases towards non-B DNA motifs. We identified a correlation between the integration sites of the latent proviruses and non-B DNA features known to potently influence gene expression (e.g., cruciform, guanine-quadruplex (G4), triplex, and Z-DNA). The reactivation potential of latent proviruses with latency reversal agents also correlated with their proximity to specific non-B DNA motifs. The perturbation of G4 structures in vitro using G4 structure-destabilizing or -stabilizing ligands resulted in a significant reduction in integration within 100 base pairs of G4 motifs. The stabilization of G4 structures increased the integration within 300–500 base pairs from G4 motifs, increased integration near transcription start sites, and increased the proportion of latently infected cells. Moreover, we showed that host lens epithelium-derived growth factor (LEDGF)/p75 and cleavage and polyadenylation specificity factor 6 (CPSF6) influenced the distribution of integration sites near several non-B DNA motifs, especially G4 DNA. Our findings identify non-B DNA motifs as important factors that influence productive and latent HIV-1 integration and the reactivation potential of latent proviruses. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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Review

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28 pages, 961 KiB

Open AccessReview

A Canadian Survey of Research on HIV-1 Latency—Where Are We Now and Where Are We Heading?

by Ana Luiza Abdalla, Gabriel Guajardo-Contreras and Andrew J. Mouland

Viruses 2024, 16(2), 229; https://doi.org/10.3390/v16020229 - 1 Feb 2024

Cited by 1 | Viewed by 2037

Abstract

Worldwide, almost 40 million people are currently living with HIV-1. The implementation of cART inhibits HIV-1 replication and reduces viremia but fails to eliminate HIV-1 from latently infected cells. These cells are considered viral reservoirs from which HIV-1 rebounds if cART is interrupted. Several efforts have been made to identify these cells and their niches. There has been little success in diminishing the pool of latently infected cells, underscoring the urgency to continue efforts to fully understand how HIV-1 establishes and maintains a latent state. Reactivating HIV-1 expression in these cells using latency-reversing agents (LRAs) has been successful, but only in vitro. This review aims to provide a broad view of HIV-1 latency, highlighting Canadian contributions toward these aims. We will summarize the research efforts conducted in Canadian labs to understand the establishment of latently infected cells and how this informs curative strategies, by reviewing how HIV latency is established, which cells are latently infected, what methodologies have been developed to characterize them, how new compounds are discovered and evaluated as potential LRAs, and what clinical trials aim to reverse latency in people living with HIV (PLWH). Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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14 pages, 2092 KiB

Open AccessReview

Hepatitis B and C in Pregnancy and Children: A Canadian Perspective

by Andrew B. Mendlowitz, Jordan J. Feld and Mia J. Biondi

Viruses 2023, 15(1), 91; https://doi.org/10.3390/v15010091 - 29 Dec 2022

Cited by 5 | Viewed by 5416

Abstract

In 2016, the World Health Organization released a plan to eliminate viral hepatitis as a public health threat by 2030. For Canada to achieve the recommended decreases in HBV- and HCV-related new diagnoses and deaths, an increase in services is urgently required. Identifying those at risk of, or who have acquired HBV and HCV, remains a challenge, especially with the emergence of new priority populations such as pregnant persons and children. Importantly, prenatal, and pediatric care are times when individuals are often already engaged with the healthcare system, leading to the potential for opportunistic or co-localized care and interventions. At present, Canada may not be maximizing all available virologic tools that could lead to increases in prevention, identification, improved management, or even cure. Here, we describe the continuum of care that includes preconception, prenatal, postpartum, and pediatric stages; and identify current global and Canadian recommendations, findings, and opportunities for improvement. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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15 pages, 858 KiB

Open AccessReview

Role of RNA Polymerase II Promoter-Proximal Pausing in Viral Transcription

by Marilyn Whelan and Martin Pelchat

Viruses 2022, 14(9), 2029; https://doi.org/10.3390/v14092029 - 13 Sep 2022

Cited by 7 | Viewed by 4230

Abstract

The promoter-proximal pause induced by the binding of the DRB sensitivity-inducing factor (DSIF) and the negative elongation factor (NELF) to RNAP II is a key step in the regulation of metazoan gene expression. It helps maintain a permissive chromatin landscape and ensures a quick transcriptional response from stimulus-responsive pathways such as the innate immune response. It is also involved in the biology of several RNA viruses such as the human immunodeficiency virus (HIV), the influenza A virus (IAV) and the hepatitis delta virus (HDV). HIV uses the pause as one of its mechanisms to enter and maintain latency, leading to the creation of viral reservoirs resistant to antiretrovirals. IAV, on the other hand, uses the pause to acquire the capped primers necessary to initiate viral transcription through cap-snatching. Finally, the HDV RNA genome is transcribed directly by RNAP II and requires the small hepatitis delta antigen to displace NELF from the polymerase and overcome the transcriptional block caused by RNAP II promoter-proximal pausing. In this review, we will discuss the RNAP II promoter-proximal pause and the roles it plays in the life cycle of RNA viruses such as HIV, IAV and HDV. Full article

(This article belongs to the Special Issue State-of-the-Art Virology Research in Canada)

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