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Viruses
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Integrase Inhibitors 2023
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Integrase Inhibitors 2023

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 8343

Special Issue Editor

Dr. Marie-Line Andreola

E-Mail Website
Guest Editor
CNRS UMR 5234 MFP, Université de Bordeaux, 33076 Bordeaux, France
Interests: retroviruses; emerging viruses; class 3 viruses; coronaviruses

Special Issue Information

Dear Colleagues,

Following viral entry, retroviruses convert the two copies of genomic RNA into double-stranded DNA that will be integrated into the cellular DNA. Integrase is the viral enzyme responsible for the catalytic steps involved in this process. In case of HIV-1 infection, integrase represents an attractive target for the development of antiviral drugs. While nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors have been used for decades in the treatment of HIV-1, integrase strand transfer inhibitors (INSTI) have been validated in HIV-1 treatment since 2007. This Special Issue is focused on the retroviral integrase, the INSTIs used in therapy and their mechanism of action, inhibitors under large stages of clinical testing, the development of other IN inhibitors that block the integration process through a distinct mechanism of action than strand transfer, and the resistance to drugs. In addition, the issue also welcomes manuscripts including novel findings with respect to targeting integrase/host factors interaction, dual inhibitors such as RNase H/integrase inhibitors, and integrases of other retroviruses aside from HIV-1. 

Dr. Marie-Line Andreola
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

  • integrase
  • inhibitors
  • resistance
  • therapy

Published Papers (4 papers)

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Research

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12 pages, 738 KiB  
Article
Trajectories of CD4+/CD8+ T-Cells Ratio 96 Weeks after Switching to Dolutegravir-Based Two-Drug Regimens: Results from a Multicenter Prospective Cohort Study
by Lucia Taramasso, Antonio Falletta, Elena Ricci, Giancarlo Orofino, Nicola Squillace, Barbara Menzaghi, Giuseppe Vittorio De Socio, Chiara Molteni, Giovanni Francesco Pellicanò, Roberto Gulminetti, Giordano Madeddu, Eleonora Sarchi, Francesca Vichi, Benedetto Maurizio Celesia, Paolo Bonfanti and Antonio Di Biagio
Viruses 2022, 14(11), 2315; https://doi.org/10.3390/v14112315 - 22 Oct 2022
Cited by 1 | Viewed by 1244
Abstract
The aim of the present study was to evaluate CD4/CD8 dynamics in patients on dolutegravir (DTG)-based two-drug regimens (2DRs) and compare them with DTG-containing triple-drug regimens (3DRs). A prospective observational study was performed in the context of the SCOLTA cohort. Experienced PWH with [...] Read more.
The aim of the present study was to evaluate CD4/CD8 dynamics in patients on dolutegravir (DTG)-based two-drug regimens (2DRs) and compare them with DTG-containing triple-drug regimens (3DRs). A prospective observational study was performed in the context of the SCOLTA cohort. Experienced PWH with HIV-RNA < 50 copies/mL were included if they were on the DTG-2DR, the DTG + tenofovir/emtricitabine (TDF/FTC) regimen, the DTG + tenofovir alafenamide (TAF)/FTC regimen, or the DTG + abacavir/lamivudine (ABC/3TC) regimen; they were followed-up for at least one year. A total of 533 PWH were enrolled, 120 in the DTG + 3TC group, 38 in the DTG + protease inhibitors (PI) group, 67 in the DTG + rilpivirine (RPV) group, 49 in the DTG + TDF/FTC group, 27 in the DTG + TAF/FTC group, and 232 in the DTG + ABC/3TC group. After one year, the CD4/CD8 ratio significantly increased in the PWH treated with DTG + 3TC (+0.08 ± 0.26), DTG + TDF/FTC (+0.1 ± 0.19), and DTG + ABC/3TC (+0.08 ± 0.25). At two years, the CD4/CD8 increase was confirmed for PWH on DTG + TDF/FTC (+0.16 ± 0.28) and DTG + ABC/3TC (+0.1 ± 0.3). In the SCOLTA cohort, PWH on 2DRs experienced a CD4/CD8 increase only in the DTG + 3TC group. Controlled studies with longer follow-up will clarify the long-term immunological and clinical impacts of DTG-2DR. Full article
(This article belongs to the Special Issue Integrase Inhibitors 2023)
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18 pages, 1797 KiB  
Article
Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors
by Parmit Kumar Singh, Wen Li, Gregory J. Bedwell, Hind J. Fadel, Eric M. Poeschla and Alan N. Engelman
Viruses 2022, 14(9), 1883; https://doi.org/10.3390/v14091883 - 26 Aug 2022
Cited by 4 | Viewed by 2077
Abstract
Allosteric integrase (IN) inhibitors (ALLINIs), which are promising preclinical compounds that engage the lens epithelium-derived growth factor (LEDGF)/p75 binding site on IN, can inhibit different aspects of human immunodeficiency virus 1 (HIV-1) replication. During the late phase of replication, ALLINIs induce aberrant IN [...] Read more.
Allosteric integrase (IN) inhibitors (ALLINIs), which are promising preclinical compounds that engage the lens epithelium-derived growth factor (LEDGF)/p75 binding site on IN, can inhibit different aspects of human immunodeficiency virus 1 (HIV-1) replication. During the late phase of replication, ALLINIs induce aberrant IN hyper-multimerization, the consequences of which disrupt IN binding to genomic RNA and virus particle morphogenesis. During the early phase of infection, ALLINIs can suppress HIV-1 integration into host genes, which is also observed in LEDGF/p75-depelted cells. Despite this similarity, the roles of LEDGF/p75 and its paralog hepatoma-derived growth factor like 2 (HDGFL2) in ALLINI-mediated integration retargeting are untested. Herein, we mapped integration sites in cells knocked out for LEDGF/p75, HDGFL2, or both factors, which revealed that these two proteins in large part account for ALLINI-mediated integration retargeting during the early phase of infection. We also determined that ALLINI-treated viruses are defective during the subsequent round of infection for integration into genes associated with speckle-associated domains, which are naturally highly targeted for HIV-1 integration. Class II IN mutant viruses with alterations distal from the LEDGF/p75 binding site moreover shared this integration retargeting phenotype. Altogether, our findings help to inform the molecular bases and consequences of ALLINI action. Full article
(This article belongs to the Special Issue Integrase Inhibitors 2023)
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Review

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31 pages, 1270 KiB  
Review
Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection
by Eline Pellaers, Anayat Bhat, Frauke Christ and Zeger Debyser
Viruses 2023, 15(1), 32; https://doi.org/10.3390/v15010032 - 21 Dec 2022
Viewed by 2071
Abstract
To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, [...] Read more.
To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, overwhelming evidence from cell culture, animal experiments and clinical data suggests that integration sites are important for retroviral replication, oncogenesis and/or latency. In this review, we will summarize the increasing knowledge of the mechanisms underlying the integration site selection of the gammaretrovirus MLV and the lentivirus HIV-1. We will discuss how host factors of the integration site selection of retroviruses may steer the development of safer viral vectors for gene therapy. Next, we will discuss how altering the integration site preference of HIV-1 using small molecules could lead to a cure for HIV-1 infection. Full article
(This article belongs to the Special Issue Integrase Inhibitors 2023)
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18 pages, 2832 KiB  
Review
Different Pathways Conferring Integrase Strand-Transfer Inhibitors Resistance
by Clémence Richetta, Nhat Quang Tu and Olivier Delelis
Viruses 2022, 14(12), 2591; https://doi.org/10.3390/v14122591 - 22 Nov 2022
Cited by 3 | Viewed by 2619
Abstract
Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections. Raltegravir (RAL) and Elvitegravir (EVG), the first generation of INSTIs used successfully in clinical treatment, are susceptible to the emergence of [...] Read more.
Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections. Raltegravir (RAL) and Elvitegravir (EVG), the first generation of INSTIs used successfully in clinical treatment, are susceptible to the emergence of viral resistance and have a high rate of cross-resistance. To counteract these resistant mutants, second-generation INSTI drugs have been developed: Dolutegravir (DTG), Cabotegravir (CAB), and Bictegravir (BIC). However, HIV is also able to develop resistance mechanisms against the second-generation of INSTIs. This review describes the mode of action of INSTIs and then summarizes and evaluates some typical resistance mutations, such as substitution and insertion mutations. The role of unintegrated viral DNA is also discussed as a new pathway involved in conferring resistance to INSTIs. This allows us to have a more detailed understanding of HIV resistance to these inhibitors, which may contribute to the development of new INSTIs in the future. Full article
(This article belongs to the Special Issue Integrase Inhibitors 2023)
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