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Viruses
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Retroviral RNA Processing
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Retroviral RNA Processing

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 27024

Special Issue Editors

Prof. Dr. Karen Beemon

E-Mail Website
Guest Editor
Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
Interests: retroviruses; Rous sarcoma virus and avian leukosis virus; viral insertional mutagenesis; cancer biology; RNA splicing; nonsense-mediated RNA decay; microRNAs; lncRNAs
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Marie-Louise Hammarskjold

E-Mail Website
Guest Editor
Myles H. Thaler Center for AIDS and Human Retrovirus Research, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
Interests: HIV; mRNA; cancer biology; virology; retroviruses; virus replication; infectious diseases/biodefense; molecular biology; post-transcriptional gene regulation

Special Issue Information

Dear Colleagues,

Retroviruses integrate their DNA genomes into host cells and are transcribed and processed mainly by the host cell machinery. However, they face some special issues regarding RNA processing that require virus-specific solutions. The unspliced primary transcript serves as the mRNA for Gag and Pol proteins, and is also the packaged RNA genome. In addition, it serves as the pre-mRNA for the spliced env mRNA, which is common to all retroviruses. Complex retroviruses use alternative splicing to generate additional gene products—with the HIV Tat and Rev proteins being prime examples. In addition, all retroviruses have to export mRNAs with retained introns from the nucleus to the cytoplasm. As such an export is restricted by the host cell, complex retroviruses have generated multiple mechanisms to export their unspliced and incompletely spliced mRNAs, using viral regulatory proteins such as Rev, Rex, and Rec to accomplish this process. In contrast, simpler retroviruses use cis-acting RNA elements known as CTEs, which directly interact with host cell proteins for the export of unspliced viral mRNA. As this RNA is both mRNA and genomic RNA, as well as pre-mRNA, specific mechanisms are also needed in order to ensure the proper distribution between these different functional classes. Regulation of the splicing and localization of viral RNA in the cell, and the interaction with the host cell RNPs, are thus critical processes in retroviral replication.

Prof. Dr. Karen Beemon
Prof. Dr. Marie-Louise Hammarskjold
Guest Editors

Manuscript Submission Information

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Keywords

  • Retroviral RNA splicing, export, translation, and localization 
  • RNPs 
  • Packaging 
  • All classes of retroviruses, including endogenous retroviruses and latent viruses

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Published Papers (7 papers)

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Research

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18 pages, 2725 KiB  
Article
HIV RGB: Automated Single-Cell Analysis of HIV-1 Rev-Dependent RNA Nuclear Export and Translation Using Image Processing in KNIME
by Edward L. Evans III, Ginger M. Pocock, Gabriel Einsdorf, Ryan T. Behrens, Ellen T. A. Dobson, Marcel Wiedenmann, Christian Birkhold, Paul Ahlquist, Kevin W. Eliceiri and Nathan M. Sherer
Viruses 2022, 14(5), 903; https://doi.org/10.3390/v14050903 - 26 Apr 2022
Cited by 3 | Viewed by 3338
Abstract
Single-cell imaging has emerged as a powerful means to study viral replication dynamics and identify sites of virus–host interactions. Multivariate aspects of viral replication cycles yield challenges inherent to handling large, complex imaging datasets. Herein, we describe the design and implementation of an [...] Read more.
Single-cell imaging has emerged as a powerful means to study viral replication dynamics and identify sites of virus–host interactions. Multivariate aspects of viral replication cycles yield challenges inherent to handling large, complex imaging datasets. Herein, we describe the design and implementation of an automated, imaging-based strategy, “Human Immunodeficiency Virus Red-Green-Blue” (HIV RGB), for deriving comprehensive single-cell measurements of HIV-1 unspliced (US) RNA nuclear export, translation, and bulk changes to viral RNA and protein (HIV-1 Rev and Gag) subcellular distribution over time. Differentially tagged fluorescent viral RNA and protein species are recorded using multicolor long-term (>24 h) time-lapse video microscopy, followed by image processing using a new open-source computational imaging workflow dubbed “Nuclear Ring Segmentation Analysis and Tracking” (NR-SAT) based on ImageJ plugins that have been integrated into the Konstanz Information Miner (KNIME) analytics platform. We describe a typical HIV RGB experimental setup, detail the image acquisition and NR-SAT workflow accompanied by a step-by-step tutorial, and demonstrate a use case wherein we test the effects of perturbing subcellular localization of the Rev protein, which is essential for viral US RNA nuclear export, on the kinetics of HIV-1 late-stage gene regulation. Collectively, HIV RGB represents a powerful platform for single-cell studies of HIV-1 post-transcriptional RNA regulation. Moreover, we discuss how similar NR-SAT-based design principles and open-source tools might be readily adapted to study a broad range of dynamic viral or cellular processes. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
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19 pages, 4515 KiB  
Article
Visualizing Rous Sarcoma Virus Genomic RNA Dimerization in the Nucleus, Cytoplasm, and at the Plasma Membrane
by Eunice C. Chen, Rebecca J. Kaddis Maldonado and Leslie J. Parent
Viruses 2021, 13(5), 903; https://doi.org/10.3390/v13050903 - 13 May 2021
Cited by 4 | Viewed by 3057
Abstract
Retroviruses are unique in that they package their RNA genomes as non-covalently linked dimers. Failure to dimerize their genomes results in decreased infectivity and reduced packaging of genomic RNA into virus particles. Two models of retrovirus genome dimerization have been characterized: in murine [...] Read more.
Retroviruses are unique in that they package their RNA genomes as non-covalently linked dimers. Failure to dimerize their genomes results in decreased infectivity and reduced packaging of genomic RNA into virus particles. Two models of retrovirus genome dimerization have been characterized: in murine leukemia virus (MLV), genomic RNA dimerization occurs co-transcriptionally in the nucleus, resulting in the preferential formation of genome homodimers; whereas in human immunodeficiency virus (HIV-1), genomic RNA dimerization occurs in the cytoplasm and at the plasma membrane, with a random distribution of heterodimers and homodimers. Although in vitro studies have identified the genomic RNA sequences that facilitate dimerization in Rous sarcoma virus (RSV), in vivo characterization of the location and preferences of genome dimerization has not been performed. In this study, we utilized three single molecule RNA imaging approaches to visualize genome dimers of RSV in cultured quail fibroblasts. The formation of genomic RNA heterodimers within cells was dependent on the presence of the dimerization initiation site (DIS) sequence in the L3 stem. Subcellular localization analysis revealed that heterodimers were present the nucleus, cytoplasm, and at the plasma membrane, indicating that genome dimers can form in the nucleus. Furthermore, single virion analysis revealed that RSV preferentially packages genome homodimers into virus particles. Therefore, the mechanism of RSV genomic RNA dimer formation appears more similar to MLV than HIV-1. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
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Review

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11 pages, 289 KiB  
Review
Retroviral RNA Processing
by Karen L. Beemon
Viruses 2022, 14(5), 1113; https://doi.org/10.3390/v14051113 - 23 May 2022
Cited by 6 | Viewed by 3221
Abstract
This review is an accompaniment to a Special Issue on “Retroviral RNA Processing”. It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, [...] Read more.
This review is an accompaniment to a Special Issue on “Retroviral RNA Processing”. It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive. However, it tries to address some of the major questions in the field with examples of how different retroviruses express their genes. It is amazing that a single primary RNA transcript can have so many possible fates: genomic RNA, unspliced mRNA, and up to 50 different alternatively spliced mRNAs. This review will discuss the sorting of RNAs for packaging or translation, RNA nuclear export mechanisms, splicing, translation, RNA modifications, and avoidance of nonsense-mediated RNA decay. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
22 pages, 2860 KiB  
Review
Anomalous HIV-1 RNA, How Cap-Methylation Segregates Viral Transcripts by Form and Function
by Kathleen Boris-Lawrie, Gatikrushna Singh, Patrick S. Osmer, Dora Zucko, Seth Staller and Xiao Heng
Viruses 2022, 14(5), 935; https://doi.org/10.3390/v14050935 - 29 Apr 2022
Cited by 11 | Viewed by 4204
Abstract
The acquisition of m7G-cap-binding proteins is now recognized as a major variable driving the form and function of host RNAs. This manuscript compares the 5′-cap-RNA binding proteins that engage HIV-1 precursor RNAs, host mRNAs, small nuclear (sn)- and small nucleolar (sno) [...] Read more.
The acquisition of m7G-cap-binding proteins is now recognized as a major variable driving the form and function of host RNAs. This manuscript compares the 5′-cap-RNA binding proteins that engage HIV-1 precursor RNAs, host mRNAs, small nuclear (sn)- and small nucleolar (sno) RNAs and sort into disparate RNA-fate pathways. Before completion of the transcription cycle, the transcription start site of nascent class II RNAs is appended to a non-templated guanosine that is methylated (m7G-cap) and bound by hetero-dimeric CBP80-CBP20 cap binding complex (CBC). The CBC is a nexus for the co-transcriptional processing of precursor RNAs to mRNAs and the snRNA and snoRNA of spliceosomal and ribosomal ribonucleoproteins (RNPs). Just as sn/sno-RNAs experience hyper-methylation of m7G-cap to trimethylguanosine (TMG)-cap, so do select HIV RNAs and an emerging cohort of mRNAs. TMG-cap is blocked from Watson:Crick base pairing and disqualified from participating in secondary structure. The HIV TMG-cap has been shown to license select viral transcripts for specialized cap-dependent translation initiation without eIF4E that is dependent upon CBP80/NCBP3. The exceptional activity of HIV precursor RNAs secures their access to maturation pathways of sn/snoRNAs, canonical and non-canonical host mRNAs in proper stoichiometry to execute the retroviral replication cycle. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
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11 pages, 900 KiB  
Review
NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells
by Chou-Zen Giam and Nagesh Pasupala
Viruses 2022, 14(5), 877; https://doi.org/10.3390/v14050877 - 23 Apr 2022
Cited by 5 | Viewed by 2854
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3–5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities [...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3–5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities are associated with cell survival and proliferation, constitutive NF-κB activation (NF-κB hyperactivation) by Tax leads to senescence and oncogenesis. Until recently, the mechanisms underlying the DNA damage and senescence induced by Tax and NF-κB were unknown. Current data indicate that NF-κB hyperactivation by Tax causes the accumulation of a nucleic acid structure known as an R-loop. R-loop excision by the transcription-coupled nucleotide excision repair (TC-NER) endonucleases, Xeroderma pigmentosum F (XPF), and XPG, in turn, promotes DNA double-strand breaks (DSBs). NF-κB blockade prevents Tax-induced R-loop accumulation, DNA damage, and senescence. In the same vein, the silencing of XPF and XPG mitigates Tax senescence, while deficiency in either or both frequently occurs in ATL of all types. ATL cells maintain constitutively active NF-κB, accumulate R-loops, and resist Tax-induced senescence. These results suggest that ATL cells must have acquired adaptive changes to prevent senescence and benefit from the survival and proliferation advantages conferred by Tax and NF-κB. In this review, the roles of R-loops in Tax- and NF-κB-induced DNA DSBs, senescence, and ATL development, and the epigenetic and genetic alterations that arise in ATL to reduce R-loop-associated DNA damage and avert senescence will be discussed. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
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10 pages, 1855 KiB  
Review
The Splice of Life: Does RNA Processing Have a Role in HIV-1 Persistence?
by Alexander O. Pasternak and Ben Berkhout
Viruses 2021, 13(9), 1751; https://doi.org/10.3390/v13091751 - 2 Sep 2021
Cited by 15 | Viewed by 2972
Abstract
Antiretroviral therapy (ART) suppresses HIV-1 replication but does not eradicate the virus. Persistence of HIV-1 latent reservoirs in ART-treated individuals is considered the main obstacle to achieving an HIV-1 cure. However, these HIV-1 reservoirs are not transcriptionally silent, and viral transcripts can be [...] Read more.
Antiretroviral therapy (ART) suppresses HIV-1 replication but does not eradicate the virus. Persistence of HIV-1 latent reservoirs in ART-treated individuals is considered the main obstacle to achieving an HIV-1 cure. However, these HIV-1 reservoirs are not transcriptionally silent, and viral transcripts can be detected in most ART-treated individuals. HIV-1 latency is regulated at the transcriptional and at multiple post-transcriptional levels. Here, we review recent insights into the possible contribution of viral RNA processing to the persistence of HIV-1 reservoirs, and discuss the clinical implications of persistence of viral RNA species in ART-treated individuals. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
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14 pages, 780 KiB  
Review
HIV-1: To Splice or Not to Splice, That Is the Question
by Ann Emery and Ronald Swanstrom
Viruses 2021, 13(2), 181; https://doi.org/10.3390/v13020181 - 26 Jan 2021
Cited by 43 | Viewed by 6107
Abstract
The transcription of the HIV-1 provirus results in only one type of transcript—full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must [...] Read more.
The transcription of the HIV-1 provirus results in only one type of transcript—full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must undergo splicing but not completely. Genomic RNA (which also functions as mRNA for the Gag and Gag/Pro/Pol precursor polyproteins) must not splice at all. HIV-1 can tolerate a surprising range in the relative abundance of individual transcript types, and a surprising amount of aberrant and even odd splicing; however, it must not over-splice, which results in the loss of full-length genomic RNA and has a dramatic fitness cost. Cells typically do not tolerate unspliced/incompletely spliced transcripts, so HIV-1 must circumvent this cell policing mechanism to allow some splicing while suppressing most. Splicing is controlled by RNA secondary structure, cis-acting regulatory sequences which bind splicing factors, and the viral protein Rev. There is still much work to be done to clarify the combinatorial effects of these splicing regulators. These control mechanisms represent attractive targets to induce over-splicing as an antiviral strategy. Finally, splicing has been implicated in latency, but to date there is little supporting evidence for such a mechanism. In this review we apply what is known of cellular splicing to understand splicing in HIV-1, and present data from our newer and more sensitive deep sequencing assays quantifying the different HIV-1 transcript types. Full article
(This article belongs to the Special Issue Retroviral RNA Processing)
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