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Viruses Aug 2022Hepatitis D is the most severe viral hepatitis. Hepatitis D virus (HDV) has a very small RNA genome with unique biological properties. It requires for infection the... (Review)
Review
Hepatitis D is the most severe viral hepatitis. Hepatitis D virus (HDV) has a very small RNA genome with unique biological properties. It requires for infection the presence of hepatitis B virus (HBV) and is transmitted parenterally, mainly by superinfection of HBsAg carriers who then develop chronic hepatitis D. HDV has been brought under control in high-income countries by the implementation of HBV vaccination, and the clinical pattern has changed to a chronic hepatitis D seen in ageing patients with advanced fibrotic disease; the disease remains a major health concern in developing countries of Africa and Asia. Every HBsAg-positive subject should be tested for HDV serum markers by reflex testing, independently of clinical status. Vaccination against HBV provides the best prophylaxis against hepatitis D. The only therapy available so far has been the poorly performing Interferon alfa; however, several new and promising therapeutic approaches are under study.
Topics: Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis D; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans
PubMed: 36016371
DOI: 10.3390/v14081749 -
Gut Sep 2021Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an... (Review)
Review
Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an unfavourable outcome, with many patients developing liver cirrhosis, liver failure and eventually hepatocellular carcinoma within 5-10 years. The identification of the HBV/HDV receptor and the development of novel in vitro and animal infection models allowed a more detailed study of the HDV life cycle in recent years, facilitating the development of specific antiviral drugs. The characterisation of HDV-specific CD4+ and CD8+T cell epitopes in untreated and treated patients also permitted a more precise understanding of HDV immunobiology and possibly paves the way for immunotherapeutic strategies to support upcoming specific therapies targeting viral or host factors. Pegylated interferon-α has been used for treating HDV patients for the last 30 years with only limited sustained responses. Here we describe novel treatment options with regard to their mode of action and their clinical effectiveness. Of those, the entry-inhibitor bulevirtide (formerly known as myrcludex B) received conditional marketing authorisation in the European Union (EU) in 2020 (Hepcludex). One additional drug, the prenylation inhibitor lonafarnib, is currently under investigation in phase III clinical trials. Other treatment strategies aim at targeting hepatitis B surface antigen, including the nucleic acid polymer REP2139Ca. These recent advances in HDV virology, immunology and treatment are important steps to make HDV a less difficult-to-treat virus and will be discussed.
Topics: Adaptive Immunity; Animals; Hepatitis D; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Immunity, Innate
PubMed: 34103404
DOI: 10.1136/gutjnl-2020-323888 -
Digestive Diseases and Sciences Aug 2023Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease.... (Review)
Review
Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.
Topics: Coinfection; Humans; Hepatitis Delta Virus; Hepatitis D; Superinfection; Hepatitis B virus
PubMed: 37338616
DOI: 10.1007/s10620-023-07960-y -
Viruses Jun 2021Hepatitis delta virus (HDV) is a defective human virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of a helper... (Review)
Review
Hepatitis delta virus (HDV) is a defective human virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of a helper virus, which provides its surface proteins to produce infectious particles. Hepatitis B virus (HBV) was so far thought to be the only helper virus described to be associated with HDV. However, recent studies showed that divergent HDV-like viruses could be detected in fishes, birds, amphibians, and invertebrates, without evidence of any HBV-like agent supporting infection. Another recent study demonstrated that HDV can be transmitted and propagated in experimental infections ex vivo and in vivo by different enveloped viruses unrelated to HBV, including hepatitis C virus (HCV) and flaviviruses such as Dengue and West Nile virus. All this new evidence, in addition to the identification of novel virus species within a large range of hosts in absence of HBV, suggests that deltaviruses may take advantage of a large spectrum of helper viruses and raises questions about HDV origins and evolution.
Topics: Animals; Evolution, Molecular; Genome, Viral; Helper Viruses; Hepatitis D; Hepatitis Delta Virus; Host Specificity; Humans; Phylogeny; Viral Proteins; Virus Replication
PubMed: 34201626
DOI: 10.3390/v13071207 -
Nature Feb 2019A stable latent reservoir for HIV-1 in resting CD4 T cells is the principal barrier to a cure. Curative strategies that target the reservoir are being tested and require...
A stable latent reservoir for HIV-1 in resting CD4 T cells is the principal barrier to a cure. Curative strategies that target the reservoir are being tested and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation may underestimate the reservoir size because one round of activation does not induce all proviruses. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection.
Topics: CD4-Positive T-Lymphocytes; Carrier State; Cell Line; DNA, Viral; Defective Viruses; HIV Infections; HIV-1; Humans; Lymphocyte Activation; Polymerase Chain Reaction; Proviruses; Virus Latency
PubMed: 30700913
DOI: 10.1038/s41586-019-0898-8 -
Viruses Feb 2022Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically,... (Review)
Review
Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically, the presence of virus-like particles has been inferred from total particle counts by microscopy, and infectious particle counts or plaque-forming-units (PFUs) by plaque assay; the resulting ratio of particles-to-PFUs is often greater than one, easily 10 or 100, indicating that most particles are non-infectious. Despite their inability to hijack cells for their reproduction, virus-like particles and the defective genomes they carry can exhibit a broad range of behaviors: interference with normal virus growth during co-infections, cell killing, and activation or inhibition of innate immune signaling. In addition, some virus-like particles become productive as their multiplicities of infection increase, a sign of cooperation between particles. Here, we review established and emerging methods to count virus-like particles and characterize their biological functions. We take a critical look at evidence for defective interfering virus genomes in natural and clinical isolates, and we review their potential as antiviral therapeutics. In short, we highlight an urgent need to better understand how virus-like genomes and particles interact with intact functional viruses during co-infection of their hosts, and their impacts on the transmission, severity, and persistence of virus-associated diseases.
Topics: Animals; Colony-Forming Units Assay; Defective Viruses; Genome, Viral; Humans; Microscopy, Electron, Transmission; Viral Plaque Assay; Virion; Virus Diseases; Virus Replication
PubMed: 35215979
DOI: 10.3390/v14020383 -
Viruses Jun 2020Hepatitis delta virus (HDV) and hepatitis B virus (HBV) are blood-borne viruses that infect human hepatocytes and cause significant liver disease. Infections with HBV... (Review)
Review
Hepatitis delta virus (HDV) and hepatitis B virus (HBV) are blood-borne viruses that infect human hepatocytes and cause significant liver disease. Infections with HBV are more damaging when there is a coinfection with HDV. The genomes and modes of replication of these two viruses are fundamentally different, except for the fact that, in nature, HDV replication is dependent upon the envelope proteins of HBV to achieve assembly and release of infectious virus particles, ones that use the same host cell receptor. This review focuses on what has been found of the various ways, natural and experimental, by which HDV particles can be assembled and released. This knowledge has implications for the prevention and treatment of HDV infections, and maybe for an understanding of the origin of HDV.
Topics: Animals; Hepatitis D; Hepatitis Delta Virus; Humans; Virus Replication
PubMed: 32560053
DOI: 10.3390/v12060648 -
The Journal of Infectious Diseases Apr 2020Hepatitis delta virus (HDV) coinfects with hepatitis B virus (HBV) causing the most severe form of viral hepatitis. However, its exact global disease burden remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hepatitis delta virus (HDV) coinfects with hepatitis B virus (HBV) causing the most severe form of viral hepatitis. However, its exact global disease burden remains largely obscure. We aim to establish the global epidemiology, infection mode-stratified disease progression, and clinical outcome of HDV infection.
METHODS
We conducted a meta-analysis with a random-effects model and performed data synthesis.
RESULTS
The pooled prevalence of HDV is 0.80% (95% confidence interval [CI], 0.63-1.00) among the general population and 13.02% (95% CI, 11.96-14.11) among HBV carriers, corresponding to 48-60 million infections globally. Among HBV patients with fulminant hepatitis, cirrhosis, or hepatocellular carcinoma, HDV prevalence is 26.75% (95% CI, 19.84-34.29), 25.77% (95% CI, 20.62-31.27), and 19.80% (95% CI, 10.97-30.45), respectively. The odds ratio (OR) of HDV infection among HBV patients with chronic liver disease compared with asymptomatic controls is 4.55 (95% CI, 3.65-5.67). Hepatitis delta virus-coinfected patients are more likely to develop cirrhosis than HBV-monoinfected patients with OR of 3.84 (95% CI, 1.79-8.24). Overall, HDV infection progresses to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years, on average.
CONCLUSIONS
Findings suggest that HDV poses a heavy global burden with rapid progression to severe liver diseases, urging effective strategies for screening, prevention, and treatment.
Topics: Developing Countries; Global Health; Hepatitis D; Hepatitis Delta Virus; Humans; Prevalence; Risk Factors
PubMed: 31778167
DOI: 10.1093/infdis/jiz633 -
Viruses May 2021Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of... (Review)
Review
Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.
Topics: Carcinogenesis; Carcinoma, Hepatocellular; Genome, Viral; Hepatitis B virus; Hepatitis D; Hepatitis D, Chronic; Hepatitis Delta Virus; Hepatocytes; Humans; Liver Cirrhosis; Liver Neoplasms; RNA, Viral; Virus Assembly
PubMed: 34064419
DOI: 10.3390/v13050830 -
Viruses Apr 2022Integrase is the retroviral protein responsible for integrating reverse transcripts into cellular genomes. Co-packaged with viral RNA and reverse transcriptase into... (Review)
Review
Integrase is the retroviral protein responsible for integrating reverse transcripts into cellular genomes. Co-packaged with viral RNA and reverse transcriptase into capsid-encased viral cores, human immunodeficiency virus 1 (HIV-1) integrase has long been implicated in reverse transcription and virion maturation. However, the underlying mechanisms of integrase in these non-catalytic-related viral replication steps have remained elusive. Recent results have shown that integrase binds genomic RNA in virions, and that mutational or pharmacological disruption of integrase-RNA binding yields eccentric virion particles with ribonucleoprotein complexes situated outside of the capsid shell. Such viruses are defective for reverse transcription due to preferential loss of integrase and viral RNA from infected target cells. Parallel research has revealed defective integrase-RNA binding and eccentric particle formation as common features of class II integrase mutant viruses, a phenotypic grouping of viruses that display defects at steps beyond integration. In light of these new findings, we propose three new subclasses of class II mutant viruses (a, b, and c), all of which are defective for integrase-RNA binding and particle morphogenesis, but differ based on distinct underlying mechanisms exhibited by the associated integrase mutant proteins. We also assess how these findings inform the role of integrase in HIV-1 particle maturation.
Topics: HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; RNA, Viral
PubMed: 35632668
DOI: 10.3390/v14050926