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Viruses
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Viral Integration
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Viral Integration

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

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 43336

Special Issue Editors

Prof. Dr. Duane P. Grandgenett

E-Mail Website
Guest Editor
Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, Saint Louis, MO, USA
Interests: retrovirus integrases; structural biology; intasomes; assembly mechanisms; concerted integration; HIV-1 strand transfer inhibitors
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Fabien Zoulim

grade E-Mail Website
Guest Editor
1. Viral Hepatitis Research Laboratory, Lyon University, Lyon, France
2. Hospices Civils de Lyon, Lyon, France
3. INSERM Unit 1052, Cancer Research Center of Lyon (CRCL), Lyon, France
Interests: hepatitis B virus; viral persistence; antiviral therapy; HBV cure

Special Issue Information

Dear Colleagues:

Retrovirus DNA integration of reverse transcribed viral RNA into cellular DNA has affected the evolution of numerous biological systems. Retroviruses also cause major human diseases, including HIV-1/AIDS and human T-cell leukemia virus type-1/adult T-cell leukemia-lymphoma. The viral integrase mediates the insertion of the two viral DNA ends into the host genome that produces persistent expression of the retrovirus genome for virus replication, as well as affecting cellular gene expression. These integration effects have significantly enhanced interest to understand the structural diversity of integrase–viral DNA complexes termed intasomes. Understanding of retrovirus integration mechanisms has been propelled by X-ray crystallography and single-particle cryo-electron microscopy of intasomes. Continued development of HIV-1 integrase strand transfer inhibitors and potential allosteric inhibitors requires high-resolution structures to combat drug-resistance mutations. The clinical use of retrovirus vectors for human gene therapies and anti-cancer thearpies will surely be enhanced in the future. The entire spectrum of retrovirus integration aspects from its harmful to beneficial effects on human health will necessitate further investigation of retrovirus integration mechanisms.

Viral genome integration is also a common feature of Hepadnaviruses. They are hepatotropic DNA viruses that replicate their DNA genome via a reverse transcriptase. The human representative, hepatitis B virus, causes major human diseases, including liver cirrhosis and hepatocellular carcinoma. By contrast to retroviruses, the viral genomic archive, which is the template for transcription and genome replication, is an episomal covalently closed circular DNA. Viral genome integration is not required for viral replication but is involved in the development of hepatocellular carcinoma. Understanding the consequences of HBV integration on the pathobiology of HBV-induced liver disease and liver oncogenesis should open new avenues to identify early predictors of liver cancer and to study novel strategies to prevent liver cancer development in chronically infected patients.

Prof. Dr. Duane P. Grandgenett
Prof. Dr. Fabien Zoulim
Guest Editors

Manuscript Submission Information

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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

  • retrovirus
  • integration
  • structural biology
  • HIV-1
  • gene therapy
  • hepadnaviruses
  • clonal expansion
  • hepatocellular carcinoma

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Published Papers (7 papers)

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Review

21 pages, 7447 KiB  
Review
RNA Interference Therapy for Chronic Hepatitis B Predicts the Importance of Addressing Viral Integration When Developing Novel Cure Strategies
by Christine I. Wooddell, Adam J. Gehring, Man-Fung Yuen and Bruce D. Given
Viruses 2021, 13(4), 581; https://doi.org/10.3390/v13040581 - 30 Mar 2021
Cited by 18 | Viewed by 4237
Abstract
Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA [...] Read more.
Chronic hepatitis B infection remains a globally important cause of morbidity and mortality and has recently undergone a renaissance in therapeutic interest with increased pre-clinical and clinical testing of new drug classes. One of the first new classes in the clinic was RNA interference agents, which have the potential to impact the entire viral life cycle by reducing all virus-produced mRNA. Early clinical testing with the first of these agents in the clinic, ARC-520, demonstrated that rapid and deep reductions in viral proteins, RNA and DNA could be produced with this approach, but also the surprising insight that HBsAg production from incomplete HBV DNA integrated into the host genome appears to play a heretofore unappreciated and important role in maintaining circulating HBsAg, thought to play a fundamental role in preventing host clearance of the virus. Thus, accounting for viral DNA integration in novel HBV treatment approaches may prove to be essential to achieving successful finite therapies of this difficult to treat chronic infection. Full article
(This article belongs to the Special Issue Viral Integration)
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21 pages, 821 KiB  
Review
HBV-Integration Studies in the Clinic: Role in the Natural History of Infection
by Teresa Pollicino and Giuseppe Caminiti
Viruses 2021, 13(3), 368; https://doi.org/10.3390/v13030368 - 26 Feb 2021
Cited by 73 | Viewed by 10161
Abstract
Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a [...] Read more.
Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge. Full article
(This article belongs to the Special Issue Viral Integration)
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11 pages, 828 KiB  
Review
The HIV-1 Capsid: From Structural Component to Key Factor for Host Nuclear Invasion
by Viviana Scoca and Francesca Di Nunzio
Viruses 2021, 13(2), 273; https://doi.org/10.3390/v13020273 - 10 Feb 2021
Cited by 16 | Viewed by 4549
Abstract
Since the discovery of HIV-1, the viral capsid has been recognized to have an important role as a structural protein that holds the viral genome, together with viral proteins essential for viral life cycle, such as the reverse transcriptase (RT) and the integrase [...] Read more.
Since the discovery of HIV-1, the viral capsid has been recognized to have an important role as a structural protein that holds the viral genome, together with viral proteins essential for viral life cycle, such as the reverse transcriptase (RT) and the integrase (IN). The reverse transcription process takes place between the cytoplasm and the nucleus of the host cell, thus the Reverse Transcription Complexes (RTCs)/Pre-integration Complexes (PICs) are hosted in intact or partial cores. Early biochemical assays failed to identify the viral CA associated to the RTC/PIC, possibly due to the stringent detergent conditions used to fractionate the cells or to isolate the viral complexes. More recently, it has been observed that some host partners of capsid, such as Nup153 and CPSF6, can only bind multimeric CA proteins organized in hexamers. Those host factors are mainly located in the nuclear compartment, suggesting the entrance of the viral CA as multimeric structure inside the nucleus. Recent data show CA complexes within the nucleus having a different morphology from the cytoplasmic ones, clearly highlighting the remodeling of the viral cores during nuclear translocation. Thus, the multimeric CA complexes lead the viral genome into the host nuclear compartment, piloting the intranuclear journey of HIV-1 in order to successfully replicate. The aim of this review is to discuss and analyze the main discoveries to date that uncover the viral capsid as a key player in the reverse transcription and PIC maturation until the viral DNA integration into the host genome. Full article
(This article belongs to the Special Issue Viral Integration)
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21 pages, 2033 KiB  
Review
Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver
by William S. Mason, Allison R. Jilbert and Samuel Litwin
Viruses 2021, 13(2), 210; https://doi.org/10.3390/v13020210 - 30 Jan 2021
Cited by 28 | Viewed by 4116
Abstract
Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years [...] Read more.
Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division. Full article
(This article belongs to the Special Issue Viral Integration)
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28 pages, 3351 KiB  
Review
Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs
by Steven J. Smith, Xue Zhi Zhao, Dario Oliveira Passos, Dmitry Lyumkis, Terrence R. Burke, Jr. and Stephen H. Hughes
Viruses 2021, 13(2), 205; https://doi.org/10.3390/v13020205 - 29 Jan 2021
Cited by 57 | Viewed by 7092
Abstract
Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are [...] Read more.
Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are effective against both wild-type (WT) HIV-1 integrase and many of the first-generation INSTI-resistant mutants. The emergence of resistance to these new second-generation INSTIs has been minimal, which has resulted in alternative treatment strategies for HIV-1 patients. Moreover, because of their high antiviral potencies and, in some cases, their bioavailability profiles, INSTIs will probably have prominent roles in pre-exposure prophylaxis (PrEP). Herein, we review the current state of the clinically relevant INSTIs and discuss the future outlook for this class of antiretrovirals. Full article
(This article belongs to the Special Issue Viral Integration)
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16 pages, 1585 KiB  
Review
Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence
by Thomas Tu, Henrik Zhang and Stephan Urban
Viruses 2021, 13(2), 180; https://doi.org/10.3390/v13020180 - 26 Jan 2021
Cited by 49 | Viewed by 6391
Abstract
Hepatitis B virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA [...] Read more.
Hepatitis B virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA has been a long-standing topic of debate. Novel in vitro models of HBV infection combined with sensitive molecular assays now enable researchers to investigate this under-characterised phenomenon with greater ease and precision. This review covers the contributions these systems have made to understanding how HBV DNA integration induces liver cancer and facilitates viral persistence. We summarise the current findings into a working model of chronic HBV infection and discuss the clinical implications of this hypothetical framework on the upcoming therapeutic strategies used to curb HBV-associated pathogenesis. Full article
(This article belongs to the Special Issue Viral Integration)
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17 pages, 3729 KiB  
Review
Jumping Ahead with Sleeping Beauty: Mechanistic Insights into Cut-and-Paste Transposition
by Matthias T. Ochmann and Zoltán Ivics
Viruses 2021, 13(1), 76; https://doi.org/10.3390/v13010076 - 8 Jan 2021
Cited by 14 | Viewed by 5390
Abstract
Sleeping Beauty (SB) is a transposon system that has been widely used as a genetic engineering tool. Central to the development of any transposon as a research tool is the ability to integrate a foreign piece of DNA into the cellular genome. Driven [...] Read more.
Sleeping Beauty (SB) is a transposon system that has been widely used as a genetic engineering tool. Central to the development of any transposon as a research tool is the ability to integrate a foreign piece of DNA into the cellular genome. Driven by the need for efficient transposon-based gene vector systems, extensive studies have largely elucidated the molecular actors and actions taking place during SB transposition. Close transposon relatives and other recombination enzymes, including retroviral integrases, have served as useful models to infer functional information relevant to SB. Recently obtained structural data on the SB transposase enable a direct insight into the workings of this enzyme. These efforts cumulatively allowed the development of novel variants of SB that offer advanced possibilities for genetic engineering due to their hyperactivity, integration deficiency, or targeting capacity. However, many aspects of the process of transposition remain poorly understood and require further investigation. We anticipate that continued investigations into the structure–function relationships of SB transposition will enable the development of new generations of transposition-based vector systems, thereby facilitating the use of SB in preclinical studies and clinical trials. Full article
(This article belongs to the Special Issue Viral Integration)
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