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Viruses
Special Issues
HIV-1 Latency: Regulation and Reversal
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HIV-1 Latency: Regulation and Reversal

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

Deadline for manuscript submissions: closed (20 December 2019) | Viewed by 22466

Special Issue Editors

Prof. Dr. Ben Berkhout

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Guest Editor
Laboratory of Experimental Virology, Department of Medical Microbiology, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
Interests: HIV-1 gene expression and latency; viral RNA structure and function; virus evolution; antiviral therapy; patient-related virus studies
Special Issues, Collections and Topics in MDPI journals
Dr. Alexander Pasternak

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Guest Editor
Laboratory of Experimental Virology, Dept Medical Microbiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
Interests: HIV-1 persistence and reservoirs, HIV-1 curative approaches, novel virological assays
Prof. Dr. Angela Ciuffi

E-Mail Website
Guest Editor
Institute of Microbiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
Interests: HIV; latency; integration; epitranscriptomics; innate immunity; single-cell
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human immunodeficiency virus type 1 (HIV-1) establishes a persistent infection, resulting in acquired immunodeficiency syndrome (AIDS) if left untreated. Around 37 million people in the world live with HIV-1 with a global HIV-1 prevalence of 0.8% among adults. Combination antiretroviral therapy (ART) has saved millions of lives, as it suppresses HIV-1 replication, blocks transmission, and improves immune responses, preventing the development of AIDS. However, ART has to be taken lifelong, is prone to side-effects, and is unable to eradicate the virus. On top of that, 40% of HIV-infected people in the world still do not have access to ART. Therefore, HIV-1 cure research has flourished in recent years, inspired by an apparent cure in a single individual.

By establishing latent infection, HIV-1 forms long-lived reservoirs in infected individuals that persist despite decades of suppressive ART and are considered the main obstacle to an HIV-1 cure. Depleting the reservoirs is therefore the principal goal of HIV-1 curative strategies. So far, the concept behind most such strategies has been the reversal of HIV-1 latency with specific compounds, which was expected to result in the switch to productive infection, with subsequent elimination of infected cells by immune-mediated clearance and/or viral cytopathic effects. However, this approach has so far demonstrated limited success in clinical trials, mainly attributed to insufficient understanding of HIV-1 latency, which prevents the development of efficient therapeutic strategies for eradication of the reservoirs. Therefore, we need to accumulate much more knowledge about the regulation of HIV-1 latency before we can design a meaningful therapeutic intervention.

In this Special Issue, we seek reviews and original research articles that discuss the latest developments in the establishment and regulation of HIV-1 latency, as well as efficient strategies for its reversal and elimination of latently infected cells.

Prof. Dr. Ben Berkhout
Dr. Alexander Pasternak
Dr. Angela Ciuffi
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.

Keywords

  • HIV-1
  • HIV-1 latency
  • HIV-1 reservoir
  • HIV-1 cure

Published Papers (5 papers)

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Research

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32 pages, 5216 KiB  
Article
Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors
by Daniel O. Pinto, Catherine DeMarino, Thy T. Vo, Maria Cowen, Yuriy Kim, Michelle L. Pleet, Robert A. Barclay, Nicole Noren Hooten, Michele K. Evans, Alonso Heredia, Elena V. Batrakova, Sergey Iordanskiy and Fatah Kashanchi
Viruses 2020, 12(8), 885; https://0-doi-org.brum.beds.ac.uk/10.3390/v12080885 - 13 Aug 2020
Cited by 8 | Viewed by 4160
Abstract
HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs [...] Read more.
HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the “shock and kill” strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells. Full article
(This article belongs to the Special Issue HIV-1 Latency: Regulation and Reversal)
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Review

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30 pages, 2111 KiB  
Review
Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy
by Roland Schwarzer, Andrea Gramatica and Warner C. Greene
Viruses 2020, 12(2), 188; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020188 - 08 Feb 2020
Cited by 10 | Viewed by 5007
Abstract
Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication [...] Read more.
Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication is a highly desirable goal, this likely represents a bridge too far for our current and foreseeable technologies. A more tractable goal involves engineering a sustained viral remission in the absence of ART––a “functional cure.” In this setting, HIV remains detectable during remission, but the size of the reservoir is small and the residual virus is effectively controlled by an engineered immune response or other intervention. Biological precedence for such an approach is found in the post-treatment controllers (PTCs), a rare group of HIV-infected individuals who, following ART withdrawal, do not experience viral rebound. PTCs are characterized by a small reservoir, greatly reduced inflammation, and the presence of a poorly understood immune response that limits viral rebound. Our goal is to devise a safe and effective means for replicating durable post-treatment control on a global scale. This requires devising methods to reduce the size of the reservoir and to control replication of this residual virus. In the following sections, we will review many of the approaches and tools that likely will be important for implementing such a “reduce and control” strategy and for achieving a PTC-like sustained HIV remission in the absence of ART. Full article
(This article belongs to the Special Issue HIV-1 Latency: Regulation and Reversal)
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12 pages, 474 KiB  
Review
Emerging PCR-Based Techniques to Study HIV-1 Reservoir Persistence
by Laurens Lambrechts, Basiel Cole, Sofie Rutsaert, Wim Trypsteen and Linos Vandekerckhove
Viruses 2020, 12(2), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020149 - 28 Jan 2020
Cited by 16 | Viewed by 3762
Abstract
While current antiretroviral therapies are able to halt HIV-1 progression, they are not curative, as an interruption of treatment usually leads to viral rebound. The persistence of this stable HIV-1 latent reservoir forms the major barrier in HIV-1 cure research. The need for [...] Read more.
While current antiretroviral therapies are able to halt HIV-1 progression, they are not curative, as an interruption of treatment usually leads to viral rebound. The persistence of this stable HIV-1 latent reservoir forms the major barrier in HIV-1 cure research. The need for a better understanding of the mechanisms behind reservoir persistence resulted in the development of several novel assays allowing to perform an extensive in-depth characterization. The objective of this review is to present an overview of the current state-of-the-art PCR-based technologies to study the replication-competent HIV-1 reservoir. Here, we outline the advantages, limitations, and clinical relevance of different approaches. Future HIV-1 eradication studies would benefit from information-rich, high-throughput assays as they provide a more efficient and standardized way of characterizing the persisting HIV-1 reservoir. Full article
(This article belongs to the Special Issue HIV-1 Latency: Regulation and Reversal)
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23 pages, 57874 KiB  
Review
The Impact of Cellular Proliferation on the HIV-1 Reservoir
by Maria C. Virgilio and Kathleen L. Collins
Viruses 2020, 12(2), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020127 - 21 Jan 2020
Cited by 9 | Viewed by 4043
Abstract
Human immunodeficiency virus (HIV) is a chronic infection that destroys the immune system in infected individuals. Although antiretroviral therapy is effective at preventing infection of new cells, it is not curative. The inability to clear infection is due to the presence of a [...] Read more.
Human immunodeficiency virus (HIV) is a chronic infection that destroys the immune system in infected individuals. Although antiretroviral therapy is effective at preventing infection of new cells, it is not curative. The inability to clear infection is due to the presence of a rare, but long-lasting latent cellular reservoir. These cells harboring silent integrated proviral genomes have the potential to become activated at any moment, making therapy necessary for life. Latently-infected cells can also proliferate and expand the viral reservoir through several methods including homeostatic proliferation and differentiation. The chromosomal location of HIV proviruses within cells influences the survival and proliferative potential of host cells. Proliferating, latently-infected cells can harbor proviruses that are both replication-competent and defective. Replication-competent proviral genomes contribute to viral rebound in an infected individual. The majority of available techniques can only assess the integration site or the proviral genome, but not both, preventing reliable evaluation of HIV reservoirs. Full article
(This article belongs to the Special Issue HIV-1 Latency: Regulation and Reversal)
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26 pages, 827 KiB  
Review
HIV-1 Latency and Latency Reversal: Does Subtype Matter?
by Indra Sarabia and Alberto Bosque
Viruses 2019, 11(12), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/v11121104 - 28 Nov 2019
Cited by 12 | Viewed by 4920
Abstract
Cells that are latently infected with HIV-1 preclude an HIV-1 cure, as antiretroviral therapy does not target this latent population. HIV-1 is highly genetically diverse, with over 10 subtypes and numerous recombinant forms circulating worldwide. In spite of this vast diversity, much of [...] Read more.
Cells that are latently infected with HIV-1 preclude an HIV-1 cure, as antiretroviral therapy does not target this latent population. HIV-1 is highly genetically diverse, with over 10 subtypes and numerous recombinant forms circulating worldwide. In spite of this vast diversity, much of our understanding of latency and latency reversal is largely based on subtype B viruses. As such, most of the development of cure strategies targeting HIV-1 are solely based on subtype B. It is currently assumed that subtype does not influence the establishment or reactivation of latent viruses. However, this has not been conclusively proven one way or the other. A better understanding of the factors that influence HIV-1 latency in all viral subtypes will help develop therapeutic strategies that can be applied worldwide. Here, we review the latest literature on subtype-specific factors that affect viral replication, pathogenesis, and, most importantly, latency and its reversal. Full article
(This article belongs to the Special Issue HIV-1 Latency: Regulation and Reversal)
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