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Nature Microbiology Jul 2019Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are... (Review)
Review
Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replication-competent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools.
Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Biological Evolution; Defective Viruses; Genome, Viral; Host-Pathogen Interactions; Humans; RNA Viruses; Virus Replication
PubMed: 31160826
DOI: 10.1038/s41564-019-0465-y -
Viruses Aug 2023Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein,... (Review)
Review
Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein, the hepatitis delta antigen (HDAg), which exists in two forms acting as nucleoproteins. HDV depends on the envelope proteins of the hepatitis B virus as a helper virus for packaging its ribonucleoprotein complex (RNP). HDV is considered the causative agent for the most severe form of viral hepatitis leading to liver fibrosis/cirrhosis and hepatocellular carcinoma. Many steps of the life cycle of HDV are still enigmatic. This review gives an overview of the complete life cycle of HDV and identifies gaps in knowledge. The focus is on the description of cellular factors being involved in the life cycle of HDV and the deregulation of cellular pathways by HDV with respect to their relevance for viral replication, morphogenesis and HDV-associated pathogenesis. Moreover, recent progress in antiviral strategies targeting cellular structures is summarized in this article.
Topics: Animals; Hepatitis Delta Virus; Hepatitis delta Antigens; Antiviral Agents; Life Cycle Stages; Liver Cirrhosis; Liver Neoplasms
PubMed: 37632029
DOI: 10.3390/v15081687 -
Antiviral Research Jul 2020Hepatitis B Virus (HBV) that infects liver parenchymal cells is responsible for severe liver diseases and co-infection with Hepatitis Delta Virus (HDV) leads to the most... (Review)
Review
Hepatitis B Virus (HBV) that infects liver parenchymal cells is responsible for severe liver diseases and co-infection with Hepatitis Delta Virus (HDV) leads to the most aggressive form of viral hepatitis. Even tough being different for their viral genome (relaxed circular partially double stranded DNA for HBV and circular RNA for HDV), HBV and HDV are both maintained as episomes in the nucleus of infected cells and use the cellular machinery for the transcription of their viral RNAs. We propose here an update on the current knowledge on HDV replication cycle that may eventually help to identify new antiviral targets.
Topics: Animals; Cell Nucleus; Coinfection; Genome, Viral; Hepatitis B virus; Hepatitis Delta Virus; Hepatitis, Viral, Human; Hepatocytes; Humans; Mice; Plasmids; Virus Replication
PubMed: 32360949
DOI: 10.1016/j.antiviral.2020.104812 -
Emerging Microbes & Infections Dec 2023In recent years, an increasing number of emerging and remerging virus outbreaks have occurred and the rapid development of vaccines against these viruses has been...
In recent years, an increasing number of emerging and remerging virus outbreaks have occurred and the rapid development of vaccines against these viruses has been crucial. Controlling the replication of premature termination codon (PTC)-containing viruses is a promising approach to generate live but replication-defective viruses that can be used for potent vaccines. Here, we used anticodon-engineered transfer RNAs (ACE-tRNAs) as powerful precision switches to control the replication of PTC-containing viruses. We showed that ACE-tRNAs display higher potency of reading through PTCs than genetic code expansion (GCE) technology. Interestingly, ACE-tRNA has a site preference that may influence its read-through efficacy. We further attempted to use ACE-tRNAs as a novel viral vaccine platform. Using a human immunodeficiency virus type 1 (HIV-1) pseudotyped virus as an RNA virus model, we found that ACE-tRNAs display high potency for read-through viral PTCs and precisely control their production. Pseudorabies virus (PRV), a herpesvirus, was used as a DNA virus model. We found that ACE-tRNAs display high potency for reading through viral PTCs and precisely controlling PTC-containing virus replication. In addition, PTC-engineered PRV completely attenuated and lost virulence in mice , and immunization with PRV containing a PTC elicited a robust immune response and provided complete protection against wild-type PRV challenge. Overall, replication-controllable PTC-containing viruses based on ACE-tRNAs provide a new strategy to rapidly attenuate virus infection and prime robust immune responses. This technology can be used as a platform for rapidly developing viral vaccines in the future.
Topics: Humans; Mice; Animals; Swine; Pseudorabies; Viral Vaccines; Herpesvirus 1, Suid; Vaccination; RNA, Transfer; Antibodies, Viral; Swine Diseases
PubMed: 36482724
DOI: 10.1080/22221751.2022.2157339 -
PeerJ 2021Viruses thrive by exploiting the cells they infect, but in order to replicate and infect other cells they must produce viral proteins. As a result, viruses are also...
Viruses thrive by exploiting the cells they infect, but in order to replicate and infect other cells they must produce viral proteins. As a result, viruses are also susceptible to exploitation by defective versions of themselves that do not produce such proteins. A defective viral genome with deletions in protein-coding genes could still replicate in cells coinfected with full-length viruses. Such a defective genome could even replicate faster due to its shorter size, interfering with the replication of the virus. We have created a synthetic defective interfering version of SARS-CoV-2, the virus causing the Covid-19 pandemic, assembling parts of the viral genome that do not code for any functional protein but enable the genome to be replicated and packaged. This synthetic defective genome replicates three times faster than SARS-CoV-2 in coinfected cells, and interferes with it, reducing the viral load of infected cells by half in 24 hours. The synthetic genome is transmitted as efficiently as the full-length genome, suggesting the location of the putative packaging signal of SARS-CoV-2. A version of such a synthetic construct could be used as a self-promoting antiviral therapy: by enabling replication of the synthetic genome, the virus would promote its own demise.
PubMed: 34249513
DOI: 10.7717/peerj.11686 -
Current HIV/AIDS Reports Jun 2022Despite suppressive antiretroviral therapy (ART), a viral reservoir persists in individuals living with HIV that can reignite systemic replication should treatment be... (Review)
Review
PURPOSE OF REVIEW
Despite suppressive antiretroviral therapy (ART), a viral reservoir persists in individuals living with HIV that can reignite systemic replication should treatment be interrupted. Understanding how HIV-1 persists through effective ART is essential to develop cure strategies to induce ART-free virus remission.
RECENT FINDINGS
The HIV-1 reservoir resides in a pool of CD4-expressing cells as a range of viral species, a subset of which is genetically intact. Recent studies suggest that the reservoir on ART is highly dynamic, with expansion and contraction of virus-infected cells over time. Overall, the intact proviral reservoir declines faster than defective viruses, suggesting enhanced immune clearance or cellular turnover. Upon treatment interruption, rebound viruses demonstrate escape from adaptive and innate immune responses, implicating these selective pressures in restriction of virus reactivation. Cure strategies employing immunotherapy are poised to test whether host immune pressure can be augmented to enhance reservoir suppression or clearance. Alternatively, genomic engineering approaches are being applied to directly eliminate intact viruses and shrink the replication-competent virus pool. New evidence suggests host immunity exerts selective pressure on reservoir viruses and clears HIV-1 infected cells over years on ART. Efforts to build on the detectable, but insufficient, reservoir clearance via empiric testing in clinical trials will inform our understanding of mechanisms of viral persistence and the direction of future cure strategies.
Topics: Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; HIV Infections; HIV Seropositivity; HIV-1; Humans; Proviruses; Viral Load; Virus Latency; Virus Replication
PubMed: 35404007
DOI: 10.1007/s11904-022-00604-2 -
Virus Research May 2019RNA virus populations are diverse due to a variety of factors, including lack of proofreading of the viral RNA-dependent RNA polymerase. These diverse viral populations... (Review)
Review
RNA virus populations are diverse due to a variety of factors, including lack of proofreading of the viral RNA-dependent RNA polymerase. These diverse viral populations include defective viruses incapable of productive infection. Recent studies have determined the existence of several modes of viral transmission outside of canonical pathways, including en bloc transmission of multiple viruses into a single host cell via membrane vesicles. Additionally, it has recently been determined that viral aggregation and bacteria can facilitate the delivery of multiple viruses to a single cell. Co-infection of RNA viruses is important since it has the potential to enhance viral fitness. Furthermore, through complementation and recombination, co-infection could potentially promote "resurrection" of otherwise defective viral genomes and has the potential to expand viral diversity.
Topics: Animals; Coinfection; Defective Viruses; Evolution, Molecular; Genome, Viral; Humans; Mice; RNA Viruses; RNA, Viral; RNA-Dependent RNA Polymerase; Recombination, Genetic; Virus Diseases; Virus Replication
PubMed: 30836113
DOI: 10.1016/j.virusres.2019.03.003 -
Viruses Dec 2018Hepatitis delta virus (HDV) is unique among animal viruses. HDV is a satellite virus of the hepatitis B virus (HBV), however it shares no sequence similarity with its... (Review)
Review
Hepatitis delta virus (HDV) is unique among animal viruses. HDV is a satellite virus of the hepatitis B virus (HBV), however it shares no sequence similarity with its helper virus and replicates independently in infected cells. HDV is the smallest human pathogenic RNA virus and shares numerous characteristics with viroids. Like viroids, HDV has a circular RNA genome which adopts a rod-like secondary structure, possesses ribozyme domains, replicates in the nucleus of infected cells by redirecting host DNA-dependent RNA polymerases (RNAP), and relies heavily on host proteins for its replication due to its small size and limited protein coding capacity. These similarities suggest an evolutionary relationship between HDV and viroids, and information on HDV could allow a better understanding of viroids and might globally help understanding the pathogenesis and molecular biology of these subviral RNAs. In this review, we discuss the host involvement in HDV replication and its implication for HDV pathogenesis.
Topics: DNA Replication; DNA-Directed RNA Polymerases; Genome, Viral; Hepatitis B virus; Hepatitis Delta Virus; Host-Pathogen Interactions; Humans; RNA; RNA, Circular; RNA, Viral; Satellite Viruses; Viroids; Virus Replication
PubMed: 30602655
DOI: 10.3390/v11010021 -
Cold Spring Harbor Perspectives in... Jul 2015Hepatitis D is caused by the hepatitis D virus (HDV), a unique RNA pathogen that requires the hepatitis B surface antigen (HBsAg) to infect. Hepatitis D is transmitted... (Review)
Review
Hepatitis D is caused by the hepatitis D virus (HDV), a unique RNA pathogen that requires the hepatitis B surface antigen (HBsAg) to infect. Hepatitis D is transmitted by the parenteral route. The main susceptible group is patients with chronic HBsAg infection who become superinfected with the virus. Hepatitis D occurs throughout the globe, but control of hepatitis B virus (HBV) in the last two decades has consistently diminished the circulation of HDV in industrialized countries. However, hepatitis D remains a medical issue for injecting drug users (IDUs), as well as immigrants from endemic HDV areas, who are reintroducing the infection in Europe.
Topics: Drug Users; Europe; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Superinfection
PubMed: 26134842
DOI: 10.1101/cshperspect.a021576 -
Communications Biology May 2021Dengue virus (DENV) is spread from human to human through the bite of the female Aedes aegypti mosquito and leads to about 100 million clinical infections yearly....
Dengue virus (DENV) is spread from human to human through the bite of the female Aedes aegypti mosquito and leads to about 100 million clinical infections yearly. Treatment options and vaccine availability for DENV are limited. Defective interfering particles (DIPs) are considered a promising antiviral approach but infectious virus contamination has limited their development. Here, a DENV-derived DIP production cell line was developed that continuously produced DENV-free DIPs. The DIPs contained and could deliver to cells a DENV serotype 2 subgenomic defective-interfering RNA, which was originally discovered in DENV infected patients. The DIPs released into cell culture supernatant were purified and could potently inhibit replication of all DENV serotypes in cells. Antiviral therapeutics are limited for many viral infection. The DIP system described could be re-purposed to make antiviral DIPs for many other RNA viruses such as SARS-CoV-2, yellow fever, West Nile and Zika viruses.
Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; Defective Viruses; Dengue; Dengue Vaccines; Dengue Virus; Genes, Reporter; HEK293 Cells; Host-Pathogen Interactions; Humans; Luminescent Proteins; RNA, Viral; Vero Cells; Viral Load; Virus Replication
PubMed: 33976375
DOI: 10.1038/s42003-021-02064-7