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Homage to Jan Svoboda: Recent Advances in Topics Pioneered by...
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Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School

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

Deadline for manuscript submissions: closed (31 October 2018) | Viewed by 77333

Special Issue Editors

Dr. Jiri Hejnar

E-Mail Website
Guest Editor
Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic
Interests: avian sarcoma/leukosis viruses; epigenetic silencing of retroviruses; receptor for retroviruses; endogenous retroviruses; syncytins; retroviral vectors; retrotransposons; transgenesis in chicken
Special Issues, Collections and Topics in MDPI journals
Dr. Tomas Ruml

E-Mail Website
Guest Editor
Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Prague, Czech Republic
Interests: retrovirus assembly and structure; retrovirus protein interactions and trafficking
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Jan Svoboda, a pioneer of retrovirology, brilliant scientist and good friend passed away on March 13 this year. He was a living legend in the fields of retrovirology, tumor viruses, and oncogenes. The scientific community will remember Svoboda not only for his seminal work. Numerous students and peers will surely remember him also for his mentorship, life-long contacts, and influence. This Special Issue intends to commemorate Jan’s scientific legacy and point out the recent progress in the topics that he established and pursued during his long and fruitful life in science. We also hope to assemble contributions from people who were influenced by Jan, either as his students or collaborators, and who now work on different topics of virology, oncology, immunology, and cell biology. We accept research articles, reviews, and, potentially, brief communications analysing Jan Svoboda's contribution to the basic concepts in virology.

The most preferred topics for research articles are virus-host interactions; trans-species virus transmission and factors of cell permissiveness to viruses; receptors for retroviruses and virus entry; virus assembly and trafficking; integration events and whole-genome approaches to retroviral localization; transcriptional control and epigenetics; latency and persistence of viral infections; retroviral pathogenesis and tumorigenesis; virus-transduced oncogenes; endogenous retroviruses; and retrotransposons. The basic models for Jan's research were Rous sarcoma virus, other avian sarcoma/leucosis viruses, and domestic chicken as a host. Therefore, we strongly encourage members of the small and vanishing ASLV and chicken community to submit their results to this Special Issue of Viruses.

Dr. Jiri Hejnar
Dr. Tomas Ruml
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Jan Svoboda scientific legacy

  • retroviruses

  • virus interactions

  • cell permissiveness for viral infection

  • retroviral pathogenesis

Published Papers (19 papers)

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Editorial

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5 pages, 209 KiB  
Editorial
The Current View of Retroviruses as Seen from the Shoulders of a Giant
by Jiří Hejnar and Tomáš Ruml
Viruses 2019, 11(9), 828; https://doi.org/10.3390/v11090828 - 05 Sep 2019
Viewed by 2504
Abstract
It has now been more than two years since we said our last goodbye to Jan Svoboda (14 [...] Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)

Research

Jump to: Editorial, Review, Other

15 pages, 1934 KiB  
Article
Avian Sarcoma and Leukosis Virus Envelope Glycoproteins Evolve to Broaden Receptor Usage Under Pressure from Entry Competitors †
by Audelia Munguia and Mark J. Federspiel
Viruses 2019, 11(6), 519; https://doi.org/10.3390/v11060519 - 05 Jun 2019
Cited by 8 | Viewed by 2538
Abstract
The subgroup A through E avian sarcoma and leukosis viruses (ASLV(A) through ASLV(E)) are a group of highly related alpharetroviruses that have evolved their envelope glycoproteins to use different receptors to enable efficient virus entry due to host resistance and/or to expand host [...] Read more.
The subgroup A through E avian sarcoma and leukosis viruses (ASLV(A) through ASLV(E)) are a group of highly related alpharetroviruses that have evolved their envelope glycoproteins to use different receptors to enable efficient virus entry due to host resistance and/or to expand host range. Previously, we demonstrated that ASLV(A) in the presence of a competitor to the subgroup A Tva receptor, SUA-rIgG immunoadhesin, evolved to use other receptor options. The selected mutant virus, RCASBP(A)Δ155–160, modestly expanded its use of the Tvb and Tvc receptors and possibly other cell surface proteins while maintaining the binding affinity to Tva. In this study, we further evolved the Δ155–160 virus with the genetic selection pressure of a soluble form of the Tva receptor that should force the loss of Tva binding affinity in the presence of the Δ155–160 mutation. Viable ASLVs were selected that acquired additional mutations in the Δ155–160 Env hypervariable regions that significantly broadened receptor usage to include Tvb and Tvc as well as retaining the use of Tva as a receptor determined by receptor interference assays. A similar deletion in the hr1 hypervariable region of the subgroup C ASLV glycoproteins evolved to broaden receptor usage when selected on Tvc-negative cells. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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23 pages, 3122 KiB  
Article
Mutations in Both the Surface and Transmembrane Envelope Glycoproteins of the RAV-2 Subgroup B Avian Sarcoma and Leukosis Virus Are Required to Escape the Antiviral Effect of a Secreted Form of the TvbS3 Receptor †
by Xueqian Yin, Deborah C. Melder, William S. Payne, Jerry B. Dodgson and Mark J. Federspiel
Viruses 2019, 11(6), 500; https://doi.org/10.3390/v11060500 - 31 May 2019
Cited by 6 | Viewed by 2337
Abstract
The subgroup A through E avian sarcoma and leukosis viruses ASLV(A) through ASLV(E) are a group of highly related alpharetroviruses that have evolved to use very different host protein families as receptors. We have exploited genetic selection strategies to force the replication-competent ASLVs [...] Read more.
The subgroup A through E avian sarcoma and leukosis viruses ASLV(A) through ASLV(E) are a group of highly related alpharetroviruses that have evolved to use very different host protein families as receptors. We have exploited genetic selection strategies to force the replication-competent ASLVs to naturally evolve and acquire mutations to escape the pressure on virus entry and yield a functional replicating virus. In this study, evolutionary pressure was exerted on ASLV(B) virus entry and replication using a secreted for of its Tvb receptor. As expected, mutations in the ASLV(B) surface glycoprotein hypervariable regions were selected that knocked out the ability for the mutant glycoprotein to bind the sTvbS3-IgG inhibitor. However, the subgroup B Rous associated virus 2 (RAV-2) also required additional mutations in the C-terminal end of the SU glycoprotein and multiple regions of TM highlighting the importance of the entire viral envelope glycoprotein trimer structure to mediate the entry process efficiently. These mutations altered the normal two-step ASLV membrane fusion process to enable infection. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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25 pages, 2875 KiB  
Article
Detailed Characterization of Early HIV-1 Replication Dynamics in Primary Human Macrophages
by David Alejandro Bejarano, Maria C. Puertas, Kathleen Börner, Javier Martinez-Picado, Barbara Müller and Hans-Georg Kräusslich
Viruses 2018, 10(11), 620; https://doi.org/10.3390/v10110620 - 10 Nov 2018
Cited by 26 | Viewed by 5004
Abstract
Macrophages are natural target cells of human immunodeficiency virus type 1 (HIV-1). Viral replication appears to be delayed in these cells compared to lymphocytes; however, little is known about the kinetics of early post-entry events. Time-of-addition experiments using several HIV-1 inhibitors and the [...] Read more.
Macrophages are natural target cells of human immunodeficiency virus type 1 (HIV-1). Viral replication appears to be delayed in these cells compared to lymphocytes; however, little is known about the kinetics of early post-entry events. Time-of-addition experiments using several HIV-1 inhibitors and the detection of reverse transcriptase (RT) products with droplet digital PCR (ddPCR) revealed that early replication was delayed in primary human monocyte-derived macrophages of several donors and peaked late after infection. Direct imaging of reverse-transcription and pre-integration complexes (RTC/PIC) by click-labeling of newly synthesized DNA further confirmed our findings and showed a concomitant shift to the nuclear stage over time. Altering the entry pathway enhanced infectivity but did not affect kinetics of viral replication. The addition of viral protein X (Vpx) enhanced productive infection and accelerated completion of reverse transcription and nuclear entry. We propose that sterile alpha motif (SAM) and histidine/aspartate (HD) domain-containing protein 1 (SAMHD1) activity lowering deoxyribonucleotide triphosphate (dNTP) pools is the principal factor delaying early HIV-1 replication in macrophages. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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12 pages, 2968 KiB  
Article
Genetic Resistance to Avian Leukosis Viruses Induced by CRISPR/Cas9 Editing of Specific Receptor Genes in Chicken Cells
by Anna Koslová, Dana Kučerová, Markéta Reinišová, Josef Geryk, Pavel Trefil and Jiří Hejnar
Viruses 2018, 10(11), 605; https://doi.org/10.3390/v10110605 - 02 Nov 2018
Cited by 25 | Viewed by 3911
Abstract
Avian leukosis viruses (ALVs), which are pathogens of concern in domestic poultry, utilize specific receptor proteins for cell entry that are both necessary and sufficient for host susceptibility to a given ALV subgroup. This unequivocal relationship offers receptors as suitable targets of selection [...] Read more.
Avian leukosis viruses (ALVs), which are pathogens of concern in domestic poultry, utilize specific receptor proteins for cell entry that are both necessary and sufficient for host susceptibility to a given ALV subgroup. This unequivocal relationship offers receptors as suitable targets of selection and biotechnological manipulation with the aim of obtaining virus-resistant poultry. This approach is further supported by the existence of natural knock-outs of receptor genes that segregate in inbred lines of chickens. We used CRISPR/Cas9 genome editing tools to introduce frame-shifting indel mutations into tva, tvc, and tvj loci encoding receptors for the A, C, and J ALV subgroups, respectively. For all three loci, the homozygous frame-shifting indels generating premature stop codons induced phenotypes which were fully resistant to the virus of respective subgroup. In the tvj locus, we also obtained in-frame deletions corroborating the importance of W38 and the four amino-acids preceding it. We demonstrate that CRISPR/Cas9-mediated knock-out or the fine editing of ALV receptor genes might be the first step in the development of virus-resistant chickens. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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21 pages, 5169 KiB  
Article
Mason-Pfizer Monkey Virus Envelope Glycoprotein Cycling and Its Vesicular Co-Transport with Immature Particles
by Petra Grznárová Prokšová, Jan Lipov, Jaroslav Zelenka, Eric Hunter, Hana Langerová, Michaela Rumlová and Tomáš Ruml
Viruses 2018, 10(10), 575; https://doi.org/10.3390/v10100575 - 20 Oct 2018
Cited by 2 | Viewed by 3690
Abstract
The envelope glycoprotein (Env) plays a crucial role in the retroviral life cycle by mediating primary interactions with the host cell. As described previously and expanded on in this paper, Env mediates the trafficking of immature Mason-Pfizer monkey virus (M-PMV) particles to the [...] Read more.
The envelope glycoprotein (Env) plays a crucial role in the retroviral life cycle by mediating primary interactions with the host cell. As described previously and expanded on in this paper, Env mediates the trafficking of immature Mason-Pfizer monkey virus (M-PMV) particles to the plasma membrane (PM). Using a panel of labeled RabGTPases as endosomal markers, we identified Env mostly in Rab7a- and Rab9a-positive endosomes. Based on an analysis of the transport of recombinant fluorescently labeled M-PMV Gag and Env proteins, we propose a putative mechanism of the intracellular trafficking of M-PMV Env and immature particles. According to this model, a portion of Env is targeted from the trans-Golgi network (TGN) to Rab7a-positive endosomes. It is then transported to Rab9a-positive endosomes and back to the TGN. It is at the Rab9a vesicles where the immature particles may anchor to the membranes of the Env-containing vesicles, preventing Env recycling to the TGN. These Gag-associated vesicles are then transported to the plasma membrane. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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7 pages, 2495 KiB  
Communication
Inhibition of v-rel-Induced Oncogenesis through microRNA Targeting
by Yongxiu Yao, Yaoyao Zhang, Na Tang, Miriam Pedrera, Zhiqiang Shen and Venugopal Nair
Viruses 2018, 10(5), 242; https://doi.org/10.3390/v10050242 - 05 May 2018
Cited by 2 | Viewed by 3245
Abstract
Several studies have shown that microRNA-targeting is an effective strategy for the selective control of tissue-tropism and pathogenesis of both DNA and RNA viruses. However, the exploitation of microRNA-targeting for the inhibition of transformation by oncogenic viruses has not been studied. The v- [...] Read more.
Several studies have shown that microRNA-targeting is an effective strategy for the selective control of tissue-tropism and pathogenesis of both DNA and RNA viruses. However, the exploitation of microRNA-targeting for the inhibition of transformation by oncogenic viruses has not been studied. The v-rel oncoprotein encoded by reticuloendotheliosis virus T strain (Rev-T) is a member of the rel/NF-κB family of transcription factors capable of transforming primary chicken spleen and bone marrow cells. Here, by engineering the target sequence of endogenous microRNA miR-142 downstream of the v-rel gene in a Replication-Competent ALV (avian leukosis virus) long terminal repeat (LTR) with a splice acceptor (RCAS) vector and using a v-rel-induced transformation model of chicken embryonic splenocyte cultures, we show that hematopoietic-specific miR-142 can inhibit the v-rel-induced transformation, and that this inhibition effect is due to the silencing of v-rel expression. The data supports the idea that microRNA-targeting can be used to inhibit viral oncogene-induced oncogenesis. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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16 pages, 3815 KiB  
Article
Does BCA3 Play a Role in the HIV-1 Replication Cycle?
by Michaela Rumlová, Ivana Křížová, Jaroslav Zelenka, Jan Weber and Tomáš Ruml
Viruses 2018, 10(4), 212; https://doi.org/10.3390/v10040212 - 20 Apr 2018
Cited by 6 | Viewed by 3490
Abstract
The cellular role of breast carcinoma-associated protein (BCA3), also known as A-kinase-interacting protein 1 (AKIP-1), is not fully understood. Recently, we reported that full-length, but not C-terminally truncated, BCA3 is incorporated into virions of Mason-Pfizer monkey virus, and that BCA3 enhances HIV-1 protease-induced [...] Read more.
The cellular role of breast carcinoma-associated protein (BCA3), also known as A-kinase-interacting protein 1 (AKIP-1), is not fully understood. Recently, we reported that full-length, but not C-terminally truncated, BCA3 is incorporated into virions of Mason-Pfizer monkey virus, and that BCA3 enhances HIV-1 protease-induced apoptosis. In the present study, we report that BCA3 is associated with purified and subtilisin-treated HIV particles. Using a combination of immune-based methods and confocal microscopy, we show that the C-terminus of BCA3 is required for packaging into HIV-1 particles. However, we were unable to identify an HIV-1 binding domain for BCA3, and we did not observe any effect of incorporated BCA3 on HIV-1 infectivity. Interestingly, the BCA3 C-terminus was previously identified as a binding site for the catalytic subunit of protein kinase A (PKAc), a cellular protein that is specifically packaged into HIV-1 particles. Based on our analysis of PKAc–BCA3 interactions, we suggest that BCA3 incorporation into HIV-1 particles is mediated by its ability to interact with PKAc. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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8 pages, 4650 KiB  
Article
Remnants of an Ancient Deltaretrovirus in the Genomes of Horseshoe Bats (Rhinolophidae)
by Tomáš Hron, Helena Farkašová, Robert J. Gifford, Petr Benda, Pavel Hulva, Tamás Görföl, Jan Pačes and Daniel Elleder
Viruses 2018, 10(4), 185; https://doi.org/10.3390/v10040185 - 10 Apr 2018
Cited by 13 | Viewed by 5651
Abstract
Endogenous retrovirus (ERV) sequences provide a rich source of information about the long-term interactions between retroviruses and their hosts. However, most ERVs are derived from a subset of retrovirus groups, while ERVs derived from certain other groups remain extremely rare. In particular, only [...] Read more.
Endogenous retrovirus (ERV) sequences provide a rich source of information about the long-term interactions between retroviruses and their hosts. However, most ERVs are derived from a subset of retrovirus groups, while ERVs derived from certain other groups remain extremely rare. In particular, only a single ERV sequence has been identified that shows evidence of being related to an ancient Deltaretrovirus, despite the large number of vertebrate genome sequences now available. In this report, we identify a second example of an ERV sequence putatively derived from a past deltaretroviral infection, in the genomes of several species of horseshoe bats (Rhinolophidae). This sequence represents a fragment of viral genome derived from a single integration. The time of the integration was estimated to be 11–19 million years ago. This finding, together with the previously identified endogenous Deltaretrovirus in long-fingered bats (Miniopteridae), suggest a close association of bats with ancient deltaretroviruses. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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Graphical abstract

17 pages, 17280 KiB  
Article
Deep Sequencing-Based Transcriptome Profiling Reveals Avian Interferon-Stimulated Genes and Provides Comprehensive Insight into Newcastle Disease Virus-Induced Host Responses
by Weiwei Liu, Xusheng Qiu, Cuiping Song, Yingjie Sun, Chunchun Meng, Ying Liao, Lei Tan, Zhuang Ding, Xiufan Liu and Chan Ding
Viruses 2018, 10(4), 162; https://doi.org/10.3390/v10040162 - 30 Mar 2018
Cited by 25 | Viewed by 4728
Abstract
Newcastle disease virus (NDV) is an avian paramyxovirus that causes significant economic losses to the poultry industry worldwide, with variations in NDV pathogenicity due to the differences in virulence between strains. However, there is limited knowledge regarding the avian innate immune response to [...] Read more.
Newcastle disease virus (NDV) is an avian paramyxovirus that causes significant economic losses to the poultry industry worldwide, with variations in NDV pathogenicity due to the differences in virulence between strains. However, there is limited knowledge regarding the avian innate immune response to NDV infection. In this study, transcriptional profiles were obtained from chick embryo fibroblasts (CEFs) that were infected with the highly virulent NDV Herts/33 strain or the nonvirulent LaSota strain using RNA-seq. This yielded 8433 transcripts that were associated with NDV infection. This list of candidate genes was then further examined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. It showed a high enrichment in the areas of cellular components and metabolic processes, with the cellular components possibly being associated with NDV pathogenicity. Among these 8433 transcripts, 3616 transcripts associated with interferon-stimulated genes (ISGs) were obtained; these transcripts are involved in metabolic processes, including protein phosphorylation and protein modification. These results provide further insight into the identification of genes that are involved in NDV infection. The global survey of changes in gene expression performed herein provides new insights into the complicated molecular mechanisms underlying virus and host interactions and will enable the use of new strategies to protect chickens against this virus. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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13 pages, 14460 KiB  
Article
Expression of TIM-3 on Plasmacytoid Dendritic Cells as a Predictive Biomarker of Decline in HIV-1 RNA Level during ART
by Albert Font-Haro, Vaclav Janovec, Tomas Hofman, Ladislav Machala, David Jilich, Zora Melkova, Jan Weber, Katerina Trejbalova and Ivan Hirsch
Viruses 2018, 10(4), 154; https://doi.org/10.3390/v10040154 - 28 Mar 2018
Cited by 3 | Viewed by 4227
Abstract
Depletion and functional impairment of circulating plasmacytoid dendritic cells (pDCs) are characteristic attributes of HIV-1-infection. The mechanism of dysfunction of pDCs is unclear. Here, we studied the development of phenotype of pDCs in a cohort of HIV-1-infected individuals monitored before the initiation and [...] Read more.
Depletion and functional impairment of circulating plasmacytoid dendritic cells (pDCs) are characteristic attributes of HIV-1-infection. The mechanism of dysfunction of pDCs is unclear. Here, we studied the development of phenotype of pDCs in a cohort of HIV-1-infected individuals monitored before the initiation and during a 9-month follow up with antiretroviral therapy (ART). Using polychromatic flow cytometry, we detected significantly higher pDC-surface expression of the HIV-1 receptor CD4, regulatory receptor BDCA-2, Fcγ receptor CD32, pDC dysfunction marker TIM-3, and the marker of killer pDC, TRAIL, in treatment-naïve HIV-1-infected individuals before initiation of ART when compared to healthy donors. After 9 months of ART, all of these markers approached but did not reach the expression levels observed in healthy donors. We found that the rate of decline in HIV-1 RNA level over the first 3 months of ART negatively correlated with the expression of TIM-3 on pDCs. We conclude that immunogenic phenotype of pDCs is not significantly restored after sustained suppression of HIV-1 RNA level in ART-treated patients and that the level of the TIM-3 expressed on pDCs in treatment naïve patients could be a predictive marker of the rate of decline in the HIV-1 RNA level during ART. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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17 pages, 1671 KiB  
Article
Proviruses with Long-Term Stable Expression Accumulate in Transcriptionally Active Chromatin Close to the Gene Regulatory Elements: Comparison of ASLV-, HIV- and MLV-Derived Vectors
by Dalibor Miklík, Filip Šenigl and Jiří Hejnar
Viruses 2018, 10(3), 116; https://doi.org/10.3390/v10030116 - 08 Mar 2018
Cited by 10 | Viewed by 4792
Abstract
Individual groups of retroviruses and retroviral vectors differ in their integration site preference and interaction with the host genome. Hence, immediately after infection genome-wide distribution of integrated proviruses is non-random. During long-term in vitro or persistent in vivo infection, the genomic position and [...] Read more.
Individual groups of retroviruses and retroviral vectors differ in their integration site preference and interaction with the host genome. Hence, immediately after infection genome-wide distribution of integrated proviruses is non-random. During long-term in vitro or persistent in vivo infection, the genomic position and chromatin environment of the provirus affects its transcriptional activity. Thus, a selection of long-term stably expressed proviruses and elimination of proviruses, which have been gradually silenced by epigenetic mechanisms, helps in the identification of genomic compartments permissive for proviral transcription. We compare here the extent and time course of provirus silencing in single cell clones of the K562 human myeloid lymphoblastoma cell line that have been infected with retroviral reporter vectors derived from avian sarcoma/leukosis virus (ASLV), human immunodeficiency virus type 1 (HIV) and murine leukaemia virus (MLV). While MLV proviruses remain transcriptionally active, ASLV proviruses are prone to rapid silencing. The HIV provirus displays gradual silencing only after an extended time period in culture. The analysis of integration sites of long-term stably expressed proviruses shows a strong bias for some genomic features—especially integration close to the transcription start sites of active transcription units. Furthermore, complex analysis of histone modifications enriched at the site of integration points to the accumulation of proviruses of all three groups in gene regulatory segments, particularly close to the enhancer loci. We conclude that the proximity to active regulatory chromatin segments correlates with stable provirus expression in various retroviral species. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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Graphical abstract

11 pages, 814 KiB  
Article
ALV Integration-Associated Hypomethylation at the TERT Promoter Locus
by Gary Lam and Karen Beemon
Viruses 2018, 10(2), 74; https://doi.org/10.3390/v10020074 - 10 Feb 2018
Cited by 3 | Viewed by 4224
Abstract
Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chicken(s) and other birds by insertional mutagenesis. The promoter region of telomerase reverse transcriptase (TERT) has been identified as an important integration site for tumorigenesis. Tumors with TERT promoter [...] Read more.
Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chicken(s) and other birds by insertional mutagenesis. The promoter region of telomerase reverse transcriptase (TERT) has been identified as an important integration site for tumorigenesis. Tumors with TERT promoter integrations are associated with increased TERT expression. The mechanism of this activation is still under investigation. We asked whether insertion of proviral DNA perturbs the epigenome of the integration site and, subsequently, impacts the regulation of neighboring genes. DNA cytosine methylation, which generally acts to suppress transcription, is one major form of epigenetic regulation. In this study, we examine allele-specific methylation patterns of genomic DNA from chicken tumors by bisulfite sequencing. We observed that alleles with TERT promoter integrations are associated with decreased methylation in the host genome near the site of integration. Our observations suggest that insertion of ALV in the TERT promoter region may induce expression of TERT through inhibition of maintenance methylation in the TERT promoter region. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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Review

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25 pages, 4175 KiB  
Review
Reverse Engineering Provides Insights on the Evolution of Subgroups A to E Avian Sarcoma and Leukosis Virus Receptor Specificity
by Mark J. Federspiel
Viruses 2019, 11(6), 497; https://doi.org/10.3390/v11060497 - 30 May 2019
Cited by 16 | Viewed by 2904
Abstract
The initial step of retrovirus entry—the interaction between the virus envelope glycoprotein trimer and a cellular receptor—is complex, involving multiple, noncontiguous determinants in both proteins that specify receptor choice, binding affinity and the ability to trigger conformational changes in the viral glycoproteins. Despite [...] Read more.
The initial step of retrovirus entry—the interaction between the virus envelope glycoprotein trimer and a cellular receptor—is complex, involving multiple, noncontiguous determinants in both proteins that specify receptor choice, binding affinity and the ability to trigger conformational changes in the viral glycoproteins. Despite the complexity of this interaction, retroviruses have the ability to evolve the structure of their envelope glycoproteins to use a different cellular protein as receptors. The highly homologous subgroup A to E Avian Sarcoma and Leukosis Virus (ASLV) glycoproteins belong to the group of class 1 viral fusion proteins with a two-step triggering mechanism that allows experimental access to intermediate structures during the fusion process. We and others have taken advantage of replication-competent ASLVs and exploited genetic selection strategies to force the ASLVs to naturally evolve and acquire envelope glycoprotein mutations to escape the pressure on virus entry and still yield a functional replicating virus. This approach allows for the simultaneous selection of multiple mutations in multiple functional domains of the envelope glycoprotein that may be required to yield a functional virus. Here, we review the ASLV family and experimental system and the reverse engineering approaches used to understand the evolution of ASLV receptor usage. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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9 pages, 339 KiB  
Review
The Importance of Being Non-Defective: A Mini Review Dedicated to the Memory of Jan Svoboda
by Peter K. Vogt
Viruses 2019, 11(1), 80; https://doi.org/10.3390/v11010080 - 18 Jan 2019
Cited by 1 | Viewed by 3178
Abstract
Jan Svoboda triggered investigations on non-defective avian sarcoma viruses. These viruses were a critical factor in the genetic understanding of retroviruses. They provided the single and unique access to the field and facilitated the discovery of the first oncogene src and of the [...] Read more.
Jan Svoboda triggered investigations on non-defective avian sarcoma viruses. These viruses were a critical factor in the genetic understanding of retroviruses. They provided the single and unique access to the field and facilitated the discovery of the first oncogene src and of the cellular origin of retroviral oncogenes. They continue to be of importance as singularly effective expression vectors that have provided insights into the molecular functions of numerous oncogenes. Combined with the contributions to the validation of the provirus hypothesis, Jan Svoboda’s investigations of non-defective avian sarcoma viruses have shaped a large and important part of retrovirology. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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12 pages, 500 KiB  
Review
Insight in HIV Integration Site Selection Provides a Block-and-Lock Strategy for a Functional Cure of HIV Infection
by Zeger Debyser, Gerlinde Vansant, Anne Bruggemans, Julie Janssens and Frauke Christ
Viruses 2019, 11(1), 12; https://doi.org/10.3390/v11010012 - 26 Dec 2018
Cited by 25 | Viewed by 6455
Abstract
Despite significant improvements in therapy, the HIV/AIDS pandemic remains an important threat to public health. Current treatments fail to eradicate HIV as proviral DNA persists in long-living cellular reservoirs, leading to viral rebound whenever treatment is discontinued. Hence, a better understanding of viral [...] Read more.
Despite significant improvements in therapy, the HIV/AIDS pandemic remains an important threat to public health. Current treatments fail to eradicate HIV as proviral DNA persists in long-living cellular reservoirs, leading to viral rebound whenever treatment is discontinued. Hence, a better understanding of viral reservoir establishment and maintenance is required to develop novel strategies to destroy latently infected cells, and/or to durably silence the latent provirus in infected cells. Whereas the mechanism of integration has been well studied from a catalytic point of view, it remains unknown how integration site selection and transcription are linked. In recent years, evidence has grown that lens epithelium-derived growth factor p75 (LEDGF/p75) is the main determinant of HIV integration site selection and that the integration site affects the transcriptional state of the provirus. LEDGINs have been developed as small molecule inhibitors of the interaction between LEDGF/p75 and integrase. Recently, it was shown that LEDGIN treatment in cell culture shifts the residual integrated provirus towards the inner nuclear compartment and out of transcription units in a dose dependent manner. This LEDGIN-mediated retargeting increased the proportion of provirus with a transcriptionally silent phenotype and the residual reservoir proved refractory to reactivation in vitro. LEDGINs provide us with a research tool to study the link between integration and transcription, a quintessential question in retrovirology. LEDGIN-mediated retargeting of the residual reservoirs provides a novel potential “block-and-lock” strategy as a functional cure of HIV infection. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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17 pages, 3182 KiB  
Review
Tackling HIV Persistence: Pharmacological versus CRISPR-Based Shock Strategies
by Gilles Darcis, Atze T. Das and Ben Berkhout
Viruses 2018, 10(4), 157; https://doi.org/10.3390/v10040157 - 29 Mar 2018
Cited by 24 | Viewed by 5832
Abstract
Jan Svoboda studied aspects of viral latency, in particular with respect to disease induction by avian RNA tumor viruses, which were later renamed as part of the extended retrovirus family. The course of retroviral pathogenesis is intrinsically linked to their unique property of [...] Read more.
Jan Svoboda studied aspects of viral latency, in particular with respect to disease induction by avian RNA tumor viruses, which were later renamed as part of the extended retrovirus family. The course of retroviral pathogenesis is intrinsically linked to their unique property of integrating the DNA copy of the retroviral genome into that of the host cell, thus forming the provirus. Retroviral latency has recently become of major clinical interest to allow a better understanding of why we can effectively block the human immunodeficiency virus type 1 (HIV-1) in infected individuals with antiviral drugs, yet never reach a cure. We will discuss HIV-1 latency and its direct consequence—the formation of long-lasting HIV-1 reservoirs. We next focus on one of the most explored strategies in tackling HIV-1 reservoirs—the “shock and kill” strategy—which describes the broadly explored pharmacological way of kicking the latent provirus, with subsequent killing of the virus-producing cell by the immune system. We furthermore present how the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system can be harnessed to reach the same objective by reactivating HIV-1 gene expression from latency. We will review the benefits and drawbacks of these different cure strategies. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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9 pages, 15283 KiB  
Perspective
Remembering Jan Svoboda: A Personal Reflection
by Robin A. Weiss
Viruses 2018, 10(4), 203; https://doi.org/10.3390/v10040203 - 18 Apr 2018
Cited by 5 | Viewed by 3927
Abstract
The Czech scientist Jan Svoboda was a pioneer of Rous sarcoma virus (RSV). In the 1960s, before the discovery of reverse transcriptase, he demonstrated the long-term persistence of the viral genome in non-productive mammalian cells, and he supported the DNA provirus hypothesis of [...] Read more.
The Czech scientist Jan Svoboda was a pioneer of Rous sarcoma virus (RSV). In the 1960s, before the discovery of reverse transcriptase, he demonstrated the long-term persistence of the viral genome in non-productive mammalian cells, and he supported the DNA provirus hypothesis of Howard Temin. He showed how the virus can be rescued in the infectious form and elucidated the replication-competent nature of the Prague strain of RSV later used for the identification of the src oncogene. His studies straddled molecular oncology and virology, and he remained an active contributor to the field until his death last year. Throughout the 50 years that I was privileged to know Svoboda as my mentor and friend, I admired his depth of scientific inquiry and his steadfast integrity in the face of political oppression. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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172 KiB  
Commentary
The Platonic Receptacle (Hypodoché), Whitehead’s Philosophy, and Genome Evolution
by Jan Svoboda and Jan Svoboda
Viruses 2017, 9(12), 381; https://doi.org/10.3390/v9120381 - 14 Dec 2017
Cited by 2 | Viewed by 3629
Abstract
The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of [...] Read more.
The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of receptacle of living organism evolution. In this article, we propose an analogy between the genetic code and a broader Platonic hypodoché, a concept that Alfred North Whitehead used to explain various aspects of science. Full article
(This article belongs to the Special Issue Homage to Jan Svoboda: Recent Advances in Topics Pioneered by his Prague School)
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