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Viruses
Special Issues
Retroviral Integration
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Retroviral Integration

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 7625

Special Issue Editors

Dr. Kristine Yoder

E-Mail Website
Guest Editor
Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH, USA
Interests: HIV; retrovirus; integrase; integration; CRISPR; chromatin
Special Issues, Collections and Topics in MDPI journals
Dr. Amit Sharma

E-Mail Website
Guest Editor
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
Interests: retrovirus-host interactions; innate immune response against retrovirus infection; molecular mechanisms of lentiviral restriction in non-human primates; SHIV/Macaque models of HIV-1 infection; HIV-1 transmission and pathogenesis

Special Issue Information

Dear Colleagues,

Integration is a defining feature of the retroviral life cycle. Retroviral integrases catalyze the covalent joining of reverse-transcribed viral DNA to the host genome. Major consequences of integration are the ability of the virus to remain latent for an extended period of time and the inability to cure patients infected with HIV-1 or HTLV-1. Advances in the purification and assembly of integrases from multiple retroviral genera have revealed that these proteins form a variety of multimeric complexes ranging from the prototype foamy virus tetramer to the Maedi visna virus dodecamer. Integrase-interacting host factors that tether viral integration complexes to chromatin and determine integration site selectivity have been identified for multiple retroviruses. The biological significance of integrase–host factor interactions is best highlighted by the use of murine leukemia virus (MLV)-based gene therapy vectors that led to leukemia in several children, which were treated to rectify primary immunodeficiencies. Tumorigenesis was due to MLV vector integration near the promoters of oncogenes and the subsequent insertional activation of oncogenes. This integration site preference is driven by the MLV integrase binding to its host factor, the BET family of proteins (Brd2, 3 and 4) that bind chromatin at promoter regions. Novel anti-retroviral therapeutics target integrase catalytic function, multimerization, and interaction with host factors. Understanding the fundamentals of integration processes and the structure/function of integrases is critical for the development of anti-retroviral therapies as well as safer gene-therapy vectors.

In this Special Issue, we invite research papers and review articles focused on all aspects of retroviral integration. Relevant topics include, but are not limited to: structure/function studies of integrase, integrase host factors, trafficking of integration complexes, integration site selection, anti-retroviral inhibitors targeting integration (not limited to integrase inhibitors), latency, and the development of retroviral vectors.

Dr. Kristine Yoder
Dr. Amit Sharma
Guest Editors

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.

Published Papers (3 papers)

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Research

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13 pages, 10590 KiB  
Article
Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors
by Long Phi Dinh, Jian Sun, Courtney D. Glenn, Krunal Patel, Julie A. Pigza, Matthew G. Donahue, Larry Yet and Jacques J. Kessl
Viruses 2022, 14(7), 1466; https://doi.org/10.3390/v14071466 - 2 Jul 2022
Cited by 3 | Viewed by 1636
Abstract
Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To [...] Read more.
Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness. Full article
(This article belongs to the Special Issue Retroviral Integration)
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10 pages, 2019 KiB  
Article
INSTIs and NNRTIs Potently Inhibit HIV-1 Polypurine Tract Mutants in a Single Round Infection Assay
by Steven J. Smith, Andrea Ferris, Xuezhi Zhao, Gary Pauly, Joel P. Schneider, Terrence R. Burke, Jr. and Stephen H. Hughes
Viruses 2021, 13(12), 2501; https://doi.org/10.3390/v13122501 - 14 Dec 2021
Cited by 7 | Viewed by 2657
Abstract
Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral compounds that prevent the insertion of a DNA copy of the viral genome into the host genome by targeting the viral enzyme integrase (IN). Dolutegravir (DTG) is a leading INSTI that is given, [...] Read more.
Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral compounds that prevent the insertion of a DNA copy of the viral genome into the host genome by targeting the viral enzyme integrase (IN). Dolutegravir (DTG) is a leading INSTI that is given, usually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), to treat HIV-1 infections. The emergence of resistance to DTG and other leading INSTIs is rare. However, there are recent reports suggesting that drug resistance mutations can occur at positions outside the integrase gene either in the HIV-1 polypurine tract (PPT) or in the envelope gene (env). Here, we used single round infectivity assays to measure the antiviral potencies of several FDA-approved INSTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) against a panel of HIV-1 PPT mutants. We also tested several of our promising INSTIs and NNRTIs in these assays. No measurable loss in potency was observed for either INSTIs or NNRTIs against the HIV-1 PPT mutants. This suggests that HIV-1 PPT mutants are not able, by themselves, to confer resistance to INSTIs or NNRTIs. Full article
(This article belongs to the Special Issue Retroviral Integration)
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Review

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17 pages, 7671 KiB  
Review
The C-Terminal Domain of HIV-1 Integrase: A Swiss Army Knife for the Virus?
by Cecilia Rocchi, Patrice Gouet, Vincent Parissi and Francesca Fiorini
Viruses 2022, 14(7), 1397; https://doi.org/10.3390/v14071397 - 27 Jun 2022
Cited by 3 | Viewed by 2503
Abstract
Retroviral integrase is a multimeric enzyme that catalyzes the integration of reverse-transcribed viral DNA into the cellular genome. Beyond integration, the Human immunodeficiency virus type 1 (HIV-1) integrase is also involved in many other steps of the viral life cycle, such as reverse [...] Read more.
Retroviral integrase is a multimeric enzyme that catalyzes the integration of reverse-transcribed viral DNA into the cellular genome. Beyond integration, the Human immunodeficiency virus type 1 (HIV-1) integrase is also involved in many other steps of the viral life cycle, such as reverse transcription, nuclear import, virion morphogenesis and proviral transcription. All these additional functions seem to depend on the action of the integrase C-terminal domain (CTD) that works as a molecular hub, interacting with many different viral and cellular partners. In this review, we discuss structural issues concerning the CTD, with particular attention paid to its interaction with nucleic acids. We also provide a detailed map of post-translational modifications and interaction with molecular partners. Full article
(This article belongs to the Special Issue Retroviral Integration)
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