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Gastroenterology Jan 2019Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with... (Review)
Review
Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis D; Hepatitis Delta Virus; Humans; Interferon-alpha; Liver Cirrhosis; Liver Neoplasms; Polyethylene Glycols; Recombinant Proteins
PubMed: 30342879
DOI: 10.1053/j.gastro.2018.09.058 -
Viruses Jul 2015Defective interfering (DI) genomes are characterised by their ability to interfere with the replication of the virus from which they were derived, and other genetically... (Review)
Review
Defective interfering (DI) genomes are characterised by their ability to interfere with the replication of the virus from which they were derived, and other genetically compatible viruses. DI genomes are synthesized by nearly all known viruses and represent a vast natural reservoir of antivirals that can potentially be exploited for use in the clinic. This review describes the application of DI virus to protect from virus-associated diseases in vivo using as an example a highly active cloned influenza A DI genome and virus that protects broadly in preclinical trials against different subtypes of influenza A and against non-influenza A respiratory viruses. This influenza A-derived DI genome protects by two totally different mechanisms: molecular interference with influenza A replication and by stimulating innate immunity that acts against non-influenza A viruses. The review considers what is needed to develop DI genomes to the point of entry into clinical trials.
Topics: Animals; Cloning, Molecular; Defective Viruses; Humans; Influenza A virus; Influenza, Human; RNA, Viral
PubMed: 26184282
DOI: 10.3390/v7072796 -
World Journal of Gastroenterology Nov 2021Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted... (Review)
Review
Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted sexually or by a parenteral route, in co-infection with HBV or by super-infection in HBV chronic carriers. HDV infection causes acute hepatitis that may progress to a fulminant form (7%-14% by super-infection and 2%-3% by HBV/HDV co-infection) or to chronic hepatitis (90% by HDV super-infection and 2%-5% by HBV/HDV co-infection), frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma (HCC). Peg-interferon alfa the only recommended therapy, clears HDV in only 10%-20% of cases and, consequently, new treatment strategies are being explored. HDV endemicity progressively decreased over the 50 years from the identification of the virus, due to improved population lifestyles and economic levels, to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs. Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic, unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments, lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.
Topics: COVID-19; Carcinoma, Hepatocellular; Coinfection; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Liver Neoplasms; Pandemics; SARS-CoV-2
PubMed: 34876788
DOI: 10.3748/wjg.v27.i42.7271 -
PLoS Pathogens Feb 2021Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have...
Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.
Topics: Aedes; Animals; Antiviral Agents; Chikungunya Fever; Chikungunya virus; Defective Viruses; Genome, Viral; Humans; Mosquito Vectors; Virus Replication
PubMed: 33556143
DOI: 10.1371/journal.ppat.1009110 -
MBio Aug 2023Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to...
Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV kinetics post-inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor-human sodium taurocholate co-transporting polypeptide (hNTCP). Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific-binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 35 minutes (standard error, SE: 6.3), binds to non-specific cells with a rate of 0.05 per hour (SE: 0.01), and returns as free virus with a rate of 0.11 per hour (SE: 0.02). Characterizing early HDV-host kinetics elucidates how quickly HDV is either cleared or bound depending on the immunological background and hNTCP presence. IMPORTANCE The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post-inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics.
Topics: Humans; Mice; Animals; Mice, Transgenic; Hepatitis Delta Virus; Kinetics; Mice, Inbred C57BL; RNA; Liver Neoplasms
PubMed: 37436080
DOI: 10.1128/mbio.01008-23 -
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 -
Virology Journal Sep 2017There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with... (Review)
Review
There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels.
Topics: Animals; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Coinfection; Genome, Viral; Genotype; Hepatitis B; Hepatitis D; Hepatitis Delta Virus; Humans; Liver Cirrhosis; Liver Neoplasms; Prognosis; RNA, Viral; Superinfection; Treatment Outcome; Virus Replication
PubMed: 28903779
DOI: 10.1186/s12985-017-0845-y -
Journal of Virology Jun 2023Influenza defective interfering (DI) viruses have long been considered promising antiviral candidates because of their ability to interfere with replication-competent...
Influenza defective interfering (DI) viruses have long been considered promising antiviral candidates because of their ability to interfere with replication-competent viruses and induce antiviral immunity. However, the mechanisms underlying DI-mediated antiviral immunity have not been extensively explored. Here, we demonstrated the interferon (IFN)-independent protection conferred by the influenza DI virus against homologous virus infection in mice deficient in type I and III IFN signaling. We identified unique host signatures responding to DI coinfection by integrating transcriptional and posttranscriptional regulatory data. DI-treated mice exhibited reduced viral transcription, less intense inflammatory and innate immune responses, and primed multiciliated cell differentiation in their lungs at an early stage of infection, even in the absence of type I or III IFNs. This increased multiciliogenesis could also be detected at the protein level via the immunofluorescence staining of lung tissue from DI-treated mice. Overall, our study provides mechanistic insight into the protection mediated by DIs, implying a unifying theme involving inflammation and multiciliogenesis in maintaining respiratory homeostasis and revealing their IFN-independent antiviral activity. During replication, the influenza virus generates genetically defective viruses. These are found in natural infections as part of the virus population within the infected host. Some versions of these defective viruses are thought to have protective effects through their interference with replication-competent viruses and induction of antiviral immunity. To better determine the mechanisms underlying the protective effects of these defective interfering (DI) viruses, we tested a DI that we previously identified with mice. Mice that were infected with a mix of wild-type influenza and DI viruses had less intense inflammatory and innate immune responses than did mice that were infected with the wild-type virus only, even when type I or III interferons, which are cytokines that play a prominent role in defending the respiratory epithelial barrier, were absent. More interestingly, the DI-infected mice had primed multiciliated cell differentiation in their lungs, indicating the potential promotion of epithelial repair by DIs.
Topics: Animals; Mice; Cell Differentiation; Defective Interfering Viruses; Interferons; Virus Replication; Orthomyxoviridae Infections; Orthomyxoviridae
PubMed: 37255439
DOI: 10.1128/jvi.00493-23 -
Viruses Nov 2020Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, with rapid progression of liver-related diseases and high rates of development of hepatocellular... (Review)
Review
Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, with rapid progression of liver-related diseases and high rates of development of hepatocellular carcinoma. The causative agent, hepatitis D virus (HDV), contains a small (approximately 1.7 kb) highly self-pairing single-strand circular RNA genome that assembles with the HDV antigen to form a ribonucleoprotein (RNP) complex. HDV depends on hepatitis B virus (HBV) envelope proteins for envelopment and de novo hepatocyte entry; however, its intracellular RNA replication is autonomous. In addition, HDV can amplify HBV independently through cell division. Cellular innate immune responses, mainly interferon (IFN) response, are crucial for controlling invading viruses, while viruses counteract these responses to favor their propagation. In contrast to HBV, HDV activates profound IFN response through the melanoma differentiation antigen 5 (MDA5) pathway. This cellular response efficiently suppresses cell-division-mediated HDV spread and, to some extent, early stages of HDV de novo infection, but only marginally impairs RNA replication in resting hepatocytes. In this review, we summarize the current knowledge on HDV structure, replication, and persistence and subsequently focus on the interplay between HDV and IFN response, including IFN activation, sensing, antiviral effects, and viral countermeasures. Finally, we discuss crosstalk with HBV.
Topics: Animals; Hepatitis B virus; Hepatitis D, Chronic; Hepatitis Delta Virus; Hepatocytes; Humans; Immunity, Innate; Interferon-Induced Helicase, IFIH1; Interferons; Mice; Virus Replication
PubMed: 33233762
DOI: 10.3390/v12111334 -
Emerging Microbes & Infections Dec 2023Hepatitis delta virus (HDV) infection accelerates the progression of chronic hepatitis B virus (HBV) infection, posing a large economic and health burden to patients. At...
BACKGROUND & AIMS
Hepatitis delta virus (HDV) infection accelerates the progression of chronic hepatitis B virus (HBV) infection, posing a large economic and health burden to patients. At present, there remains a lack of accurate and portable detection methods for HDV RNA. Here, we aim to establish a convenient, rapid, highly sensitive and specific method to detect HDV RNA using CRISPR-Cas13a technology.
METHODS
We established fluorescence (F) and lateral flow strip (L) assays based on CRISPR-Cas13a combined with RT-PCR and RT-RAA for HDV RNA detection, respectively. we conducted a cohort study of 144 patients with HDV-IgG positive to evaluate the CRISPR-Cas13a diagnostic performance for identifying HDV in clinical samples, compared to RT-qPCR and RT-ddPCR.
RESULTS
For synthetic HDV RNA plasmids, the sensitivity of RT-PCR-CRISPR-based fluorescence assays was 1 copy/μL, higher than that of RT-qPCR (10 copies/μL) and RT-ddPCR (10 copies/μL); for HDV RNA-positive samples, the sensitivity of RT-RAA-CRISPR-based fluorescence and lateral flow strip assays was 10 copies/μL, as low as that of RT-qPCR and RT-ddPCR, and the assay took only approximately 85 min. Additionally, the positivity rates of anti-HDV IgG-positive samples detected by the RT-qPCR, RT-ddPCR, RT-PCR-CRISPR fluorescence and RT-RAA-CRISPR lateral flow strip methods were 66.7% (96/144), 76.4% (110/144), 81.9% (118/144), and 72.2% (104/144), respectively.
CONCLUSIONS
We developed a highly sensitive and specific, as well as a portable and easy CRISPR-based assay for the detection of HDV RNA, which could be a prospective measure for monitoring the development of HDV infection and evaluating the therapeutic effect.
Topics: Humans; Hepatitis Delta Virus; Hepatitis B, Chronic; Cohort Studies; Prospective Studies; RNA, Viral; Immunoglobulin G; Sensitivity and Specificity
PubMed: 37882492
DOI: 10.1080/22221751.2023.2276337