A Meeting of Minds: In Recognition of the Contributions of Randall J. Cohrs

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

Deadline for manuscript submissions: closed (1 May 2022) | Viewed by 76013

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Division of Infectious Diseases/Virology, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
Interests: varicella-zoster virus; pediatric infectious disease
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Department of Neurology, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO 80045, USA

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Department of Microbiology, Immunology, and Pathology College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
Interests: flavivirus; dengue virus; zika virus; cyclin dependent kinase 8; walleye dermal sarcoma virus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Randy Cohrs was a major contributor to the field of Alphahepresvirus latency, especially of Varicella Zoster Virus. His work extended from his deep compassion for afflicted patients and their families and took him to the cutting edge of molecular mechanisms of virus transcription control. He helped bring practicable therapies and vaccines to the clinic. He coupled his work with patient samples to in vitro systems and advanced next-generation sequencing techniques to bring clarity to the control of Alphaherpesvirus gene expression in disease.

Randy also worked outside the herpesvirus field both to share information and to learn from the work of others on various virus models. He wanted to know what others thought and he went to extraordinary measures to make it possible for them to share their work. While particularly focused on students (of all ages and disciplines), he trained everyone he met in the art of communication. He practiced that and forced others to practice it as well. To that end, Randy’s contributions to science extend well beyond his chosen field. Whether it was the International Herpes Workshop, the Rocky Mountain Branch of the American Society for Microbiology, the Rocky Mountain Virology Meeting, or, his favorite, the Colorado Alphaherpesvirus Latency Society, he dedicated himself fully to scientific communication. The results have come to play in many fields as a result of his introduction of diverse persons and personalities in convivial and, for him, joyous interactions. He was a magnanimous, kind and charitable man who broke down all the barriers to scientific communication…as often as he possibly could.

Viruses has offered to publish a Special Issue in memory of Randy. In considering topics for this issue, it would be difficult to imagine one that would not interest Randy. Although the role of insulators on latent VZV genomes was near and dear to Randy, original research reports, reviews and commentaries on Randy’s contributions to various investigations are welcome.

Dr. Joel Rovnak
Guest Editor

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Published Papers (25 papers)

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Editorial

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5 pages, 1028 KiB  
Editorial
The Enduring Legacy of Randall Cohrs: A Meeting of the Minds in the Rocky Mountains
by Charles Grose, Joel Rovnak and Ravi Mahalingam
Viruses 2022, 14(5), 915; https://doi.org/10.3390/v14050915 - 28 Apr 2022
Viewed by 1520
Abstract
Randall Cohrs established the Colorado Alphaherpesvirus Latency Society (CALS) in 2011 [...] Full article
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Research

Jump to: Editorial, Review, Other

18 pages, 4041 KiB  
Article
Genetic Adaptation by Dengue Virus Serotype 2 to Enhance Infection of Aedes aegypti Mosquito Midguts
by Steven M. Erb, Siritorn Butrapet, John T. Roehrig, Claire Y.-H. Huang and Carol D. Blair
Viruses 2022, 14(7), 1569; https://doi.org/10.3390/v14071569 - 19 Jul 2022
Cited by 3 | Viewed by 2019
Abstract
Dengue viruses (DENVs), serotypes 1–4, are arthropod-borne viruses transmitted to humans by mosquitoes, primarily Aedes aegypti. The transmission cycle begins when Ae. aegypti ingest blood from a viremic human and the virus infects midgut epithelial cells. In studying viruses derived from the DENV2 [...] Read more.
Dengue viruses (DENVs), serotypes 1–4, are arthropod-borne viruses transmitted to humans by mosquitoes, primarily Aedes aegypti. The transmission cycle begins when Ae. aegypti ingest blood from a viremic human and the virus infects midgut epithelial cells. In studying viruses derived from the DENV2 infectious clone 30P-NBX, we found that when the virus was delivered to female Ae. aegypti in an infectious blood meal, the midgut infection rate (MIR) was very low. To determine if adaptive mutations in the DENV2 envelope (E) glycoprotein could be induced to increase the MIR, we serially passed 30P-NBX in Ae. aegypti midguts. After four passages, a single, non-conservative mutation in E protein domain II (DII) nucleotide position 1300 became dominant, resulting in replacement of positively-charged amino acid lysine (K) at position 122 with negatively-charged glutamic acid (E; K122E) and a significantly-enhanced MIR. Site directed mutagenesis experiments showed that reducing the positive charge of this surface-exposed region of the E protein DII correlated with improved Ae. aegypti midgut infection. Full article
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7 pages, 203 KiB  
Article
Silent Reactivation of Varicella Zoster Virus in Pregnancy: Implications for Maintenance of Immunity to Varicella
by Mirella Mourad, Michael Gershon, Satish K. Mehta, Brian E. Crucian, Nicole Hubbard, Jing Zhang and Anne Gershon
Viruses 2022, 14(7), 1438; https://doi.org/10.3390/v14071438 - 30 Jun 2022
Cited by 2 | Viewed by 1721
Abstract
We encountered two cases of varicella occurring in newborn infants. Because the time between birth and the onset of the illness was much shorter than the varicella incubation period, the cases suggested that the infection was maternally acquired, despite the fact that neither [...] Read more.
We encountered two cases of varicella occurring in newborn infants. Because the time between birth and the onset of the illness was much shorter than the varicella incubation period, the cases suggested that the infection was maternally acquired, despite the fact that neither mother experienced clinical zoster. Thus, we tested the hypothesis that VZV frequently reactivates asymptomatically in late pregnancy. The appearance of DNA-encoding VZV genes in saliva was used as an indicator of reactivation. Saliva was collected from 5 women in the first and 14 women in the third trimesters of pregnancy and analyzed at two different sites, at one using nested PCR and at the other using quantitative PCR (qPCR). No VZV DNA was detected at either site in the saliva of women during the first trimester; however, VZV DNA was detected in the majority of samples of saliva (11/12 examined by nested PCR; 7/10 examined by qPCR) during the third trimester. These observations suggest that VZV reactivation occurs commonly during the third trimester of pregnancy. It is possible that this phenomenon, which remains in most patients below the clinical threshold, provides an endogenous boost to immunity and, thus, is beneficial. Full article
7 pages, 589 KiB  
Communication
Variable Gene Expression in Human Ganglia Latently Infected with Varicella-Zoster Virus
by Peter G. E. Kennedy and Paul Montague
Viruses 2022, 14(6), 1250; https://doi.org/10.3390/v14061250 - 9 Jun 2022
Cited by 1 | Viewed by 2869
Abstract
Varicella-Zoster virus (VZV) is a pathogenic human herpes virus that causes varicella (“chicken pox”) as a primary infection, following which it becomes latent in neuronal cells in human peripheral ganglia. It may then reactivate to cause herpes zoster (“shingles”). Defining the pattern of [...] Read more.
Varicella-Zoster virus (VZV) is a pathogenic human herpes virus that causes varicella (“chicken pox”) as a primary infection, following which it becomes latent in neuronal cells in human peripheral ganglia. It may then reactivate to cause herpes zoster (“shingles”). Defining the pattern of VZV gene expression during latency is an important issue, and four highly expressed VZV genes were first identified by Randall Cohrs in 1996 using cDNA libraries. Further studies from both his and other laboratories, including our own, have suggested that viral gene expression may be more widespread than previously thought, but a confounding factor has always been the possibility of viral reactivation after death in tissues obtained even at 24 h post-mortem. Recent important studies, which Randall Cohrs contributed to, have clarified this issue by studying human trigeminal ganglia at 6 h after death using RNA-Seq methodology when a novel spliced latency-associated VZV transcript (VLT) was found to be mapped antisense to the viral transactivator gene 61. Viral gene expression could be induced by a VLT-ORF 63 fusion transcript when VZV reactivated from latency. Prior detection by several groups of ORF63 in post-mortem-acquired TG is very likely to reflect detection of the VLT-ORF63 fusion and not canonical ORF63. The contributions to the VZV latency field by Randall Cohrs have been numerous and highly significant. Full article
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17 pages, 1594 KiB  
Article
Simian Varicella Virus Pathogenesis in Skin during Varicella and Zoster
by Ravi Mahalingam, Brittany Feia, Colin Coleman, Kusala Anupindi, Pratush Saravanan, Amalia Luthens, Amalia Bustillos, Arpita Das, Eileen de Haro, Lara Doyle-Meyers, Jayme Looper, Andrew N. Bubak, Christy S. Niemeyer, Brent Palmer, Maria A. Nagel and Vicki Traina-Dorge
Viruses 2022, 14(6), 1167; https://doi.org/10.3390/v14061167 - 27 May 2022
Cited by 1 | Viewed by 2642
Abstract
Primary simian varicella virus (SVV) infection and reactivation in nonhuman primates is a valuable animal model in the study of varicella zoster virus disease [varicella (chickenpox) and herpes zoster (shingles)]. To understand SVV pathogenesis in skin, we inoculated 10 rhesus macaques with SVV, [...] Read more.
Primary simian varicella virus (SVV) infection and reactivation in nonhuman primates is a valuable animal model in the study of varicella zoster virus disease [varicella (chickenpox) and herpes zoster (shingles)]. To understand SVV pathogenesis in skin, we inoculated 10 rhesus macaques with SVV, resulting in varicella rash. After the establishment of latency, eight of the monkeys were immunosuppressed using tacrolimus with or without irradiation and prednisone and two monkeys were not immunosuppressed. Zoster rash developed in all immunosuppressed monkeys and in one non-immunosuppressed monkey. Five monkeys had recurrent zoster. During varicella and zoster, SVV DNA in skin scrapings ranged from 50 to 107 copies/100 ng of total DNA and 2–127 copies/100 ng of total DNA, respectively. Detection of SVV DNA in blood during varicella was more frequent and abundant compared to that of zoster. During varicella and zoster, SVV antigens colocalized with neurons expressing β-III tubulin in epidermis, hair follicles, and sweat glands, suggesting axonal transport of the virus. Together, we have demonstrated that both SVV DNA and antigens can be detected in skin lesions during varicella and zoster, providing the basis for further studies on SVV skin pathogenesis, including immune responses and mechanisms of peripheral spread. Full article
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13 pages, 2000 KiB  
Communication
HLA-B*57:01 Complexed to a CD8 T-Cell Epitope from the HSV-2 ICP22 Protein Binds NK and T Cells through KIR3DL1
by Kerry J. Laing, Victoria L. Campbell, Lichun Dong and David M. Koelle
Viruses 2022, 14(5), 1019; https://doi.org/10.3390/v14051019 - 11 May 2022
Viewed by 1977
Abstract
HLA-B*57:01 is an HLA allelic variant associated with positive outcomes during viral infections through interactions with T cells and NK cells, but severe disease in persons treated with the anti-HIV-1 drug abacavir. The role of HLA-B*57:01 in the context of HSV infection is [...] Read more.
HLA-B*57:01 is an HLA allelic variant associated with positive outcomes during viral infections through interactions with T cells and NK cells, but severe disease in persons treated with the anti-HIV-1 drug abacavir. The role of HLA-B*57:01 in the context of HSV infection is unknown. We identified an HLA-B*57:01-restricted CD8 T-cell epitope in the ICP22 (US1) protein of HSV-2. CD8 T cells reactive to the HSV-2 ICP22 epitope recognized the orthologous HSV-1 peptide, but not closely related peptides in human IFNL2 or IFNL3. Abacavir did not alter the CD8 T-cell recognition of the HSV or self-derived peptides. Unexpectedly, a tetramer of HSV-2 ICP22 epitope (228–236) and HLA-B*57:01 bound both CD8 T cells and NK cells. Tetramer specificity for KIR3DL1 was confirmed using KIR3DL1 overexpression on non-human primate cells lacking human KIR and studies with blocking anti-KIR3DL1 antibody. Interaction with KIR3DL1 was generalizable to donors lacking the HLA-B*57:01 genotype or HSV seropositivity. These findings suggest a mechanism for the recognition of HSV infection by NK cells or KIR-expressing T cells via KIR3DL1. Full article
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13 pages, 1363 KiB  
Article
Studies of Infection and Experimental Reactivation by Recombinant VZV with Mutations in Virally-Encoded Small Non-Coding RNA
by Punam Bisht, Biswajit Das, Tatiana Borodianskiy-Shteinberg, Paul R. Kinchington and Ronald S. Goldstein
Viruses 2022, 14(5), 1015; https://doi.org/10.3390/v14051015 - 10 May 2022
Viewed by 1641
Abstract
Locked-nucleotide analog antagonists (LNAA) to four varicella zoster virus small non-coding RNA (VZVsncRNA 10–13) derived from the mRNA of the open reading frame (ORF) 61 gene individually reduce VZV replication in epithelial cells and fibroblasts. To study the potential roles VZVsncRNA 10–13 have [...] Read more.
Locked-nucleotide analog antagonists (LNAA) to four varicella zoster virus small non-coding RNA (VZVsncRNA 10–13) derived from the mRNA of the open reading frame (ORF) 61 gene individually reduce VZV replication in epithelial cells and fibroblasts. To study the potential roles VZVsncRNA 10–13 have in neuronal infection we generated two recombinant VZV; one in which 8 nucleotides were changed in VZVsncRNA10 without altering the encoded residues of ORF61 (VZVsnc10MUT) and a second containing a 12-nucleotide deletion of the sequence common to VZVsncRNA12 and 13, located in the ORF61 mRNA leader sequence (VZVsnc12-13DEL). Both were developed from a VZV BAC with a green fluorescent protein (GFP) reporter fused to the N terminal of the capsid protein encoded by ORF23. The growth of both mutant VZV in epithelial cells and fibroblasts was similar to that of the parental recombinant virus. Both mutants established productive infections and experimental latency in neurons derived from human embryonic stem cells (hESC). However, neurons that were latently infected with both VZV mutant viruses showed impaired ability to reactivate when given stimuli that successfully reactivated the parental virus. These results suggest that these VZVsncRNA may have a role in VZV latency maintenance and/or reactivation. The extension of these studies and confirmation of such roles could potentially inform the development of a non-reactivating, live VZV vaccine. Full article
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27 pages, 11404 KiB  
Article
Two Consecutive Prolines in the Fusion Peptide of Murine β-Coronavirus Spike Protein Predominantly Determine Fusogenicity and May Be Essential but Not Sufficient to Cause Demyelination
by Abass Alao Safiriyu, Manmeet Singh, Abhinoy Kishore, Vaishali Mulchandani, Dibyajyoti Maity, Amrutamaya Behera, Bidisha Sinha, Debnath Pal and Jayasri Das Sarma
Viruses 2022, 14(4), 834; https://doi.org/10.3390/v14040834 - 17 Apr 2022
Cited by 1 | Viewed by 2351
Abstract
Combined in silico, in vitro, and in vivo comparative studies between isogenic-recombinant Mouse-Hepatitis-Virus-RSA59 and its proline deletion mutant, revealed a remarkable contribution of centrally located two consecutive prolines (PP) from Spike protein fusion peptide (FP) in enhancing virus fusogenic and hepato-neuropathogenic potential. To [...] Read more.
Combined in silico, in vitro, and in vivo comparative studies between isogenic-recombinant Mouse-Hepatitis-Virus-RSA59 and its proline deletion mutant, revealed a remarkable contribution of centrally located two consecutive prolines (PP) from Spike protein fusion peptide (FP) in enhancing virus fusogenic and hepato-neuropathogenic potential. To deepen our understanding of the underlying factors, we extend our studies to a non-fusogenic parental virus strain RSMHV2 (P) with a single proline in the FP and its proline inserted mutant, RSMHV2 (PP). Comparative in vitro and in vivo studies between virus strains RSA59(PP), RSMHV2 (P), and RSMHV2 (PP) in the FP demonstrate that the insertion of one proline significantly resulted in enhancing the virus fusogenicity, spread, and consecutive neuropathogenesis. Computational studies suggest that the central PP in Spike FP induces a locally ordered, compact, and rigid structure of the Spike protein in RSMHV2 (PP) compared to RSMHV2 (P), but globally the Spike S2-domain is akin to the parental strain RSA59(PP), the latter being the most flexible showing two potential wells in the energy landscape as observed from the molecular dynamics studies. The critical location of two central prolines of the FP is essential for fusogenicity and pathogenesis making it a potential site for designing antiviral. Full article
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20 pages, 2839 KiB  
Article
Development of Robust Varicella Zoster Virus Luciferase Reporter Viruses for In Vivo Monitoring of Virus Growth and Its Antiviral Inhibition in Culture, Skin, and Humanized Mice
by Megan G. Lloyd, Michael B. Yee, Joseph S. Flot, Dongmei Liu, Brittany W. Geiler, Paul R. Kinchington and Jennifer F. Moffat
Viruses 2022, 14(4), 826; https://doi.org/10.3390/v14040826 - 15 Apr 2022
Cited by 3 | Viewed by 2716
Abstract
There is a continued need to understand varicella-zoster virus (VZV) pathogenesis and to develop more effective antivirals, as it causes chickenpox and zoster. As a human-restricted alphaherpesvirus, the use of human skin in culture and mice is critical in order to reveal the [...] Read more.
There is a continued need to understand varicella-zoster virus (VZV) pathogenesis and to develop more effective antivirals, as it causes chickenpox and zoster. As a human-restricted alphaherpesvirus, the use of human skin in culture and mice is critical in order to reveal the important VZV genes that are required for pathogenesis but that are not necessarily observed in the cell culture. We previously used VZV-expressing firefly luciferase (fLuc), under the control of the constitutively active SV40 promoter (VZV-BAC-Luc), to measure the VZV spread in the same sample. However, the fLuc expression was independent of viral gene expression and viral DNA replication programs. Here, we developed robust reporter VZV viruses by using bacterial artificial chromosome (BAC) technology, expressing luciferase from VZV-specific promoters. We also identified two spurious mutations in VZV-BAC that were corrected for maximum pathogenesis. VZV with fLuc driven by ORF57 showed superior growth in cells, human skin explants, and skin xenografts in mice. The ORF57-driven luciferase activity had a short half-life in the presence of foscarnet. This background was then used to investigate the roles for ORF36 (thymidine kinase (TK)) and ORF13 (thymidylate synthase (TS)) in skin. The studies reveal that VZV-∆TS had increased sensitivity to brivudine and was highly impaired for skin replication. This is the first report of a phenotype that is associated with the loss of TS. Full article
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14 pages, 1902 KiB  
Article
Dermatitis during Spaceflight Associated with HSV-1 Reactivation
by Satish K. Mehta, Moriah L. Szpara, Bridgette V. Rooney, Douglass M. Diak, Mackenzie M. Shipley, Daniel W. Renner, Stephanie S. Krieger, Mayra A. Nelman-Gonzalez, Sara R. Zwart, Scott M. Smith and Brian E. Crucian
Viruses 2022, 14(4), 789; https://doi.org/10.3390/v14040789 - 11 Apr 2022
Cited by 16 | Viewed by 2950
Abstract
Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic [...] Read more.
Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report, for the first time, a case of HSV-1 skin rash (dermatitis) occurring during long-duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3 × 104 copies/ng DNA, respectively. Post-mission saliva samples continued to have a high infectious HSV-1 load (1.67 × 107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.9% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines), and biochemical profile markers, including vitamin/mineral status and bone metabolism, are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis to determine viral etiology and guide treatment. Full article
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25 pages, 3046 KiB  
Article
Human Cytomegalovirus Infection Elicits Global Changes in Host Transcription by RNA Polymerases I, II, and III
by Christopher B. Ball, Mrutyunjaya Parida, Ming Li, Benjamin M. Spector, Gustavo A. Suarez, Jeffery L. Meier and David H. Price
Viruses 2022, 14(4), 779; https://doi.org/10.3390/v14040779 - 9 Apr 2022
Cited by 8 | Viewed by 2400
Abstract
How human cytomegalovirus (HCMV) infection impacts the transcription of the host genome remains incompletely understood. Here, we examine the global consequences of infection of primary human foreskin fibroblasts (HFFs) on transcription by RNA polymerase I, II, and III over the course of a [...] Read more.
How human cytomegalovirus (HCMV) infection impacts the transcription of the host genome remains incompletely understood. Here, we examine the global consequences of infection of primary human foreskin fibroblasts (HFFs) on transcription by RNA polymerase I, II, and III over the course of a lytic infection using PRO-Seq. The expected rapid induction of innate immune response genes is observed with specific subsets of genes exhibiting dissimilar expression kinetics. We find minimal effects on Pol II initiation, but increased rates of the release of paused Pol II into productive elongation are detected by 24 h postinfection and pronounced at late times postinfection. Pol I transcription increases during infection and we provide evidence for a potential Pol I elongation control mechanism. Pol III transcription of tRNA genes is dramatically altered, with many induced and some repressed. All effects are partially dependent on viral genome replication, suggesting a link to viral mRNA levels and/or a viral early–late or late gene product. Changes in tRNA transcription are connected to distinct alterations in the chromatin state around tRNA genes, which were probed with high-resolution DFF-ChIP. Additionally, evidence is provided that the Pol III PIC stably contacts an upstream −1 nucleosome. Finally, we compared and contrasted our HCMV data with results from published experiments with HSV-1, EBV, KSHV, and MHV68. We report disparate effects on Pol II transcription and potentially similar effects on Pol III transcription. Full article
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17 pages, 2914 KiB  
Article
Tripartite-Motif 21 (TRIM21) Deficiency Results in a Modest Loss of Herpes Simplex Virus (HSV)-1 Surveillance in the Trigeminal Ganglia Following Cornea Infection
by Amanda Berube, Grzegorz B. Gmyrek, Derek J. Royer and Daniel J. J. Carr
Viruses 2022, 14(3), 589; https://doi.org/10.3390/v14030589 - 12 Mar 2022
Cited by 5 | Viewed by 2471
Abstract
Tripartite-motif 21 (TRIM21) is thought to regulate the type I interferon (IFN) response to virus pathogens and serve as a cytosolic Fc receptor for immunoglobulin. Since herpes simplex virus (HSV)-1 is sensitive to type I IFN and neutralizing antibody, we investigated the role [...] Read more.
Tripartite-motif 21 (TRIM21) is thought to regulate the type I interferon (IFN) response to virus pathogens and serve as a cytosolic Fc receptor for immunoglobulin. Since herpes simplex virus (HSV)-1 is sensitive to type I IFN and neutralizing antibody, we investigated the role of TRIM21 in response to ocular HSV-1 infection in mice. In comparison to wild type (WT) mice, TRIM21 deficient (TRIM21 KO) mice were found to be no more susceptible to ocular HSV-1 infection than WT animals, in terms of infectious virus recovered in the cornea. Similar pathology, in terms of neovascularization, opacity, and loss of peripheral vision function, was observed in both WT and TRIM21 KO mice. However, TRIM21 KO mice did possess a significant increase in infectious virus recovered in the trigeminal ganglia, in comparison to the WT animals. The increased susceptibility was not due to changes in HSV-1-specific CD4+ or CD8+ T cell numbers or functional capabilities, or in changes in type I IFN or IFN-inducible gene expression. In summary, the absence of TRIM21 results in a modest, but significant, increase in HSV-1 titers recovered from the TG of TRIM21 KO mice during acute infection, by a mechanism yet to be determined. Full article
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24 pages, 3719 KiB  
Article
Antiviral Targeting of Varicella Zoster Virus Replication and Neuronal Reactivation Using CRISPR/Cas9 Cleavage of the Duplicated Open Reading Frames 62/71
by Betty W. Wu, Michael B. Yee, Ronald S. Goldstein and Paul R. Kinchington
Viruses 2022, 14(2), 378; https://doi.org/10.3390/v14020378 - 12 Feb 2022
Cited by 2 | Viewed by 2960
Abstract
Varicella Zoster Virus (VZV) causes Herpes Zoster (HZ), a common debilitating and complicated disease affecting up to a third of unvaccinated populations. Novel antiviral treatments for VZV reactivation and HZ are still in need. Here, we evaluated the potential of targeting the replicating [...] Read more.
Varicella Zoster Virus (VZV) causes Herpes Zoster (HZ), a common debilitating and complicated disease affecting up to a third of unvaccinated populations. Novel antiviral treatments for VZV reactivation and HZ are still in need. Here, we evaluated the potential of targeting the replicating and reactivating VZV genome using Clustered Regularly Interspaced Short Palindromic Repeat-Cas9 nucleases (CRISPR/Cas9) delivered by adeno-associated virus (AAV) vectors. After AAV serotype and guide RNA (gRNA) optimization, we report that a single treatment with AAV2-expressing Staphylococcus aureus CRISPR/Cas9 (saCas9) with gRNA to the duplicated and essential VZV genes ORF62/71 (AAV2-62gRsaCas9) greatly reduced VZV progeny yield and cell-to-cell spread in representative epithelial cells and in lytically infected human embryonic stem cell (hESC)-derived neurons. In contrast, AAV2-62gRsaCas9 did not reduce the replication of a recombinant virus mutated in the ORF62 targeted sequence, establishing that antiviral effects were a consequence of VZV-genome targeting. Delivery to latently infected and reactivation-induced neuron cultures also greatly reduced infectious-virus production. These results demonstrate the potential of AAV-delivered genome editors to limit VZV productive replication in epithelial cells, infected human neurons, and upon reactivation. The approach could be developed into a strategy for the treatment of VZV disease and virus spread in HZ. Full article
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17 pages, 5520 KiB  
Article
Visualization of Marek’s Disease Virus Genomes in Living Cells during Lytic Replication and Latency
by Tereza Vychodil, Darren J. Wight, Mariana Nascimento, Fabian Jolmes, Thomas Korte, Andreas Herrmann and Benedikt B. Kaufer
Viruses 2022, 14(2), 287; https://doi.org/10.3390/v14020287 - 29 Jan 2022
Cited by 1 | Viewed by 3154
Abstract
Visualization of the herpesvirus genomes during lytic replication and latency is mainly achieved by fluorescence in situ hybridization (FISH). Unfortunately, this technique cannot be used for the real-time detection of viral genome in living cells. To facilitate the visualization of the Marek’s disease [...] Read more.
Visualization of the herpesvirus genomes during lytic replication and latency is mainly achieved by fluorescence in situ hybridization (FISH). Unfortunately, this technique cannot be used for the real-time detection of viral genome in living cells. To facilitate the visualization of the Marek’s disease virus (MDV) genome during all stages of the virus lifecycle, we took advantage of the well-established tetracycline operator/repressor (TetO/TetR) system. This system consists of a fluorescently labeled TetR (TetR-GFP) that specifically binds to an array of tetO sequences. This tetO repeat array was first inserted into the MDV genome (vTetO). Subsequently, we fused TetR-GFP via a P2a self-cleaving peptide to the C-terminus of the viral interleukin 8 (vIL8), which is expressed during lytic replication and latency. Upon reconstitution of this vTetO-TetR virus, fluorescently labeled replication compartments were detected in the nucleus during lytic replication. After validating the specificity of the observed signal, we used the system to visualize the genesis and mobility of the viral replication compartments. In addition, we assessed the infection of nuclei in syncytia as well as lytic replication and latency in T cells. Taken together, we established a system allowing us to track the MDV genome in living cells that can be applied to many other DNA viruses. Full article
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12 pages, 2869 KiB  
Article
Acyl-Coa Thioesterases: A Rheostat That Controls Activated Fatty Acids Modulates Dengue Virus Serotype 2 Replication
by Laura A. St Clair, Stephanie A. Mills, Elena Lian, Paul S. Soma, Aritra Nag, Caroline Montgomery, Gabriela Ramirez, Nunya Chotiwan, Rebekah C. Gullberg and Rushika Perera
Viruses 2022, 14(2), 240; https://doi.org/10.3390/v14020240 - 25 Jan 2022
Cited by 3 | Viewed by 3414
Abstract
During infection with dengue viruses (DENVs), the lipid landscape within host cells is significantly altered to assemble membrane platforms that support viral replication and particle assembly. Fatty acyl-CoAs are key intermediates in the biosynthesis of complex lipids that form these membranes. They also [...] Read more.
During infection with dengue viruses (DENVs), the lipid landscape within host cells is significantly altered to assemble membrane platforms that support viral replication and particle assembly. Fatty acyl-CoAs are key intermediates in the biosynthesis of complex lipids that form these membranes. They also function as key signaling lipids in the cell. Here, we carried out loss of function studies on acyl-CoA thioesterases (ACOTs), a family of enzymes that hydrolyze fatty acyl-CoAs to free fatty acids and coenzyme A, to understand their influence on the lifecycle of DENVs. The loss of function of the type I ACOTs 1 (cytoplasmic) and 2 (mitochondrial) together significantly increased DENV serotype 2 (DENV2) viral replication and infectious particle release. However, isolated knockdown of mitochondrial ACOT2 significantly decreased DENV2 protein translation, genome replication, and infectious virus release. Furthermore, loss of ACOT7 function, a mitochondrial type II ACOT, similarly suppressed DENV2. As ACOT1 and ACOT2 are splice variants, these data suggest that functional differences and substrate specificities due to the location (cytosol and mitochondria, respectively) of these proteins may account for the differences in DENV2 infection phenotype. Additionally, loss of mitochondrial ACOT2 and ACOT7 expression also altered the expression of several ACOTs located in multiple organelle compartments within the cell, highlighting a complex relationship between ACOTs in the DENV2 virus lifecycle. Full article
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19 pages, 4395 KiB  
Article
Mutagenesis of the Varicella-Zoster Virus Genome Demonstrates That VLT and VLT-ORF63 Proteins Are Dispensable for Lytic Infection
by Shirley E. Braspenning, Robert Jan Lebbink, Daniel P. Depledge, Claudia M. E. Schapendonk, Laura A. Anderson, Georges M. G. M. Verjans, Tomohiko Sadaoka and Werner J. D. Ouwendijk
Viruses 2021, 13(11), 2289; https://doi.org/10.3390/v13112289 - 16 Nov 2021
Cited by 2 | Viewed by 3349
Abstract
Primary varicella-zoster virus (VZV) infection leads to varicella and the establishment of lifelong latency in sensory ganglion neurons. Reactivation of latent VZV causes herpes zoster, which is frequently associated with chronic pain. Latent viral gene expression is restricted to the VZV latency-associated transcript [...] Read more.
Primary varicella-zoster virus (VZV) infection leads to varicella and the establishment of lifelong latency in sensory ganglion neurons. Reactivation of latent VZV causes herpes zoster, which is frequently associated with chronic pain. Latent viral gene expression is restricted to the VZV latency-associated transcript (VLT) and VLT-ORF63 (VLT63) fusion transcripts. Since VLT and VLT63 encode proteins that are expressed during lytic infection, we investigated whether pVLT and pVLT-ORF63 are essential for VZV replication by performing VZV genome mutagenesis using CRISPR/Cas9 and BAC technologies. We first established that CRISPR/Cas9 can efficiently mutate VZV genomes in lytically VZV-infected cells through targeting non-essential genes ORF8 and ORF11 and subsequently show recovery of viable mutant viruses. By contrast, the VLT region was markedly resistant to CRISPR/Cas9 editing. Whereas most mutants expressed wild-type or N-terminally altered versions of pVLT and pVLT-ORF63, only a minority of the resulting mutant viruses lacked pVLT and pVLT-ORF63 coding potential. Growth curve analysis showed that pVLT/pVLT-ORF63 negative viruses were viable, but impaired in growth in epithelial cells. We confirmed this phenotype independently using BAC-derived pVLT/pVLT-ORF63 negative and repaired viruses. Collectively, these data demonstrate that pVLT and/or pVLT-ORF63 are dispensable for lytic VZV replication but promote efficient VZV infection in epithelial cells. Full article
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15 pages, 1621 KiB  
Article
Meningitis Caused by the Live Varicella Vaccine Virus: Metagenomic Next Generation Sequencing, Immunology Exome Sequencing and Cytokine Multiplex Profiling
by Prashanth S. Ramachandran, Michael R. Wilson, Gaud Catho, Geraldine Blanchard-Rohner, Nicoline Schiess, Randall J. Cohrs, David Boutolleau, Sonia Burrel, Tetsushi Yoshikawa, Anne Wapniarski, Ethan H. Heusel, John E. Carpenter, Wallen Jackson, Bradley A. Ford and Charles Grose
Viruses 2021, 13(11), 2286; https://doi.org/10.3390/v13112286 - 16 Nov 2021
Cited by 13 | Viewed by 3171
Abstract
Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing [...] Read more.
Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3–4 weeks before onset of vaccine meningitis may be a risk factor in some cases. Full article
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Review

Jump to: Editorial, Research, Other

20 pages, 1799 KiB  
Review
Impact of Cultured Neuron Models on α-Herpesvirus Latency Research
by Angus C. Wilson
Viruses 2022, 14(6), 1209; https://doi.org/10.3390/v14061209 - 2 Jun 2022
Cited by 8 | Viewed by 2916
Abstract
A signature trait of neurotropic α-herpesviruses (α-HV) is their ability to establish stable non-productive infections of peripheral neurons termed latency. This specialized gene expression program is the foundation of an evolutionarily successful strategy to ensure lifelong persistence in the host. Various physiological stresses [...] Read more.
A signature trait of neurotropic α-herpesviruses (α-HV) is their ability to establish stable non-productive infections of peripheral neurons termed latency. This specialized gene expression program is the foundation of an evolutionarily successful strategy to ensure lifelong persistence in the host. Various physiological stresses can induce reactivation in a subset of latently-infected neurons allowing a new cycle of viral productive cycle gene expression and synthesis of infectious virus. Recurring reactivation events ensure transmission of the virus to new hosts and contributes to pathogenesis. Efforts to define the molecular basis of α-HV latency and reactivation have been notoriously difficult because the neurons harboring latent virus in humans and in experimentally infected live-animal models, are rare and largely inaccessible to study. Increasingly, researchers are turning to cultured neuron infection models as simpler experimental platforms from which to explore latency and reactivation at the molecular level. In this review, I reflect on the strengths and weaknesses of existing neuronal models and briefly summarize the important mechanistic insights these models have provided. I also discuss areas where prioritization will help to ensure continued progress and integration. Full article
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14 pages, 1204 KiB  
Review
The Biology of Varicella-Zoster Virus Replication in the Skin
by Cristina Tommasi and Judith Breuer
Viruses 2022, 14(5), 982; https://doi.org/10.3390/v14050982 - 6 May 2022
Cited by 10 | Viewed by 8007
Abstract
The replication of varicella-zoster virus (VZV) in skin is critical to its pathogenesis and spread. Primary infection causes chickenpox, which is characterised by centrally distributed skin blistering lesions that are rich in infectious virus. Cell-free virus in the cutaneous blistering lesions not only [...] Read more.
The replication of varicella-zoster virus (VZV) in skin is critical to its pathogenesis and spread. Primary infection causes chickenpox, which is characterised by centrally distributed skin blistering lesions that are rich in infectious virus. Cell-free virus in the cutaneous blistering lesions not only spreads to cause further cases, but infects sensory nerve endings, leading to the establishment of lifelong latency in sensory and autonomic ganglia. The reactivation of virus to cause herpes zoster is again characterised by localised painful skin blistering rash containing infectious virus. The development of in vitro and in vivo models of VZV skin replication has revealed aspects of VZV replication and pathogenesis in this important target organ and improved our understanding of the vaccine strain vOKa attenuation. In this review, we outline the current knowledge on VZV interaction with host signalling pathways, the viral association with proteins associated with epidermal terminal differentiation, and how these interconnect with the VZV life cycle to facilitate viral replication and shedding. Full article
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27 pages, 5665 KiB  
Review
Antiviral Drug Discovery for the Treatment of COVID-19 Infections
by Teresa I. Ng, Ivan Correia, Jane Seagal, David A. DeGoey, Michael R. Schrimpf, David J. Hardee, Elizabeth L. Noey and Warren M. Kati
Viruses 2022, 14(5), 961; https://doi.org/10.3390/v14050961 - 4 May 2022
Cited by 42 | Viewed by 6420
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex. Full article
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8 pages, 913 KiB  
Review
Rational Design of a Skin- and Neuro-Attenuated Live Varicella Vaccine: A Review and Future Perspectives
by Wei Wang, Dequan Pan, Tong Cheng and Hua Zhu
Viruses 2022, 14(5), 848; https://doi.org/10.3390/v14050848 - 20 Apr 2022
Cited by 3 | Viewed by 2260
Abstract
Primary varicella-zoster virus (VZV) infection causes varicella, which remains a prominent public health concern in children. Current varicella vaccines adopt the live-attenuated Oka strain, vOka, which retains the ability to infect neurons, establish latency and reactivate, leading to vaccine-associated zoster in some vaccinees. [...] Read more.
Primary varicella-zoster virus (VZV) infection causes varicella, which remains a prominent public health concern in children. Current varicella vaccines adopt the live-attenuated Oka strain, vOka, which retains the ability to infect neurons, establish latency and reactivate, leading to vaccine-associated zoster in some vaccinees. Therefore, it is necessary to develop a safer next-generation varicella vaccine to help reduce vaccine hesitancy. This paper reviews the discovery and identification of the skin- and neuro-tropic factor, the open reading frame 7 (ORF7) of VZV, as well as the development of a skin- and neuro-attenuated live varicella vaccine comprising an ORF7-deficient mutant, v7D. This work could provide insights into the research of novel virus vaccines based on functional genomics and reverse genetics. Full article
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12 pages, 940 KiB  
Review
Comparative Analysis of the Simian Varicella Virus and Varicella Zoster Virus Genomes
by Wayne L. Gray
Viruses 2022, 14(5), 844; https://doi.org/10.3390/v14050844 - 19 Apr 2022
Cited by 1 | Viewed by 2290
Abstract
Varicella zoster virus (VZV) and simian varicella virus (SVV) cause varicella (chickenpox) in children and nonhuman primates, respectively. After resolution of acute disease, the viruses establish latent infection in neural ganglia, after which they may reactivate to cause a secondary disease, such as [...] Read more.
Varicella zoster virus (VZV) and simian varicella virus (SVV) cause varicella (chickenpox) in children and nonhuman primates, respectively. After resolution of acute disease, the viruses establish latent infection in neural ganglia, after which they may reactivate to cause a secondary disease, such as herpes zoster. SVV infection of nonhuman primates provides a model to investigate VZV pathogenesis and antiviral strategies. The VZV and SVV genomes are similar in size and structure and share 70–75% DNA homology. SVV and VZV DNAs are co-linear in gene arrangement with the exception of the left end of the viral genomes. Viral gene expression is regulated into immediate early, early, and late transcription during in vitro and in vivo infection. During viral latency, VZV and SVV gene expression is limited to transcription of a viral latency-associated transcript (VLT). VZV and SVV are closely related alphaherpesviruses that likely arose from an ancestral varicella virus that evolved through cospeciation into species-specific viruses. Full article
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13 pages, 3021 KiB  
Review
Distinguishing Features Common to Dual Fatal Herpes Simplex Virus Infections That Occur in Both a Pregnant Woman and Her Newborn Infant
by Nathan B. Price and Kelly E. Wood
Viruses 2021, 13(12), 2542; https://doi.org/10.3390/v13122542 - 18 Dec 2021
Cited by 3 | Viewed by 4418
Abstract
Deaths from herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are rare. A major exception is perinatally acquired HSV-1 or HSV-2 infection where the neonatal death rate is substantial. Fatal HSV infection also occurs occasionally in pregnant women. [...] Read more.
Deaths from herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are rare. A major exception is perinatally acquired HSV-1 or HSV-2 infection where the neonatal death rate is substantial. Fatal HSV infection also occurs occasionally in pregnant women. The goal of this review is to enumerate the reports that describe dual deaths of both a pregnant woman and her newborn from a herpesvirus infection. A total of 15 reports were found in the medical literature, of which five described pregnant women with HSV encephalitis and 10 described women with disseminated HSV infection. When the virus was typed, most cases of dual mother/newborn deaths were caused by HSV-2. Of interest, in two situations caused by HSV-1, the pregnant woman probably acquired her primary HSV-1 infection from one of her children and not by sexual transmission. Complete genomic sequencing was performed on one set of HSV-1 isolates collected from mother (blood) and newborn (blood and skin). The mother’s strain and the newborn’s skin strain were 98.9% identical. When the newborn’s two strains were compared, they were 97.4% identical. Only one mother was tested by the HerpeSelect IgG antibody kit. During the nine days of her undiagnosed disseminated infection preceding her death, her serology was negative. In summary, although dual mother/newborn deaths from HSV infection are rare, they continue to be reported as recently as 2017. Full article
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Other

8 pages, 6704 KiB  
Obituary
Meeting in Mind and a Smile on the Face: A Tribute to Dr. Randall J Cohrs
by Jayasri Das Sarma
Viruses 2022, 14(6), 1124; https://doi.org/10.3390/v14061124 - 24 May 2022
Viewed by 1395
Abstract
It is my privilege to have a mentor cum friend like Prof [...] Full article
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25 pages, 1815 KiB  
Conference Report
The 21st Annual Meeting of the Rocky Mountain Virology Association
by Laura A. St Clair, Ali L. Brehm, Shelby Cagle, Tillie Dunham, Jonathan Faris, Paul Gendler, Monica E. Graham, Sandra L. Quackenbush, Joel Rovnak and Rushika Perera
Viruses 2021, 13(12), 2392; https://doi.org/10.3390/v13122392 - 29 Nov 2021
Cited by 1 | Viewed by 2490
Abstract
Nestled within the Rocky Mountain National Forest, 114 scientists and students gathered at Colorado State University’s Mountain Campus for this year’s 21st annual Rocky Mountain National Virology Association meeting. This 3-day retreat consisted of 31 talks and 30 poster presentations discussing advances in [...] Read more.
Nestled within the Rocky Mountain National Forest, 114 scientists and students gathered at Colorado State University’s Mountain Campus for this year’s 21st annual Rocky Mountain National Virology Association meeting. This 3-day retreat consisted of 31 talks and 30 poster presentations discussing advances in research pertaining to viral and prion diseases. The keynote address provided a timely discussion on zoonotic coronaviruses, lessons learned, and the path forward towards predicting, preparing, and preventing future viral disease outbreaks. Other invited speakers discussed advances in SARS-CoV-2 surveillance, molecular interactions involved in flavivirus genome assembly, evaluation of ethnomedicines for their efficacy against infectious diseases, multi-omic analyses to define risk factors associated with long COVID, the role that interferon lambda plays in control of viral pathogenesis, cell-fusion-dependent pathogenesis of varicella zoster virus, and advances in the development of a vaccine platform against prion diseases. On behalf of the Rocky Mountain Virology Association, this report summarizes select presentations. Full article
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