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Viruses Jan 2022Treatment options for HDV have been limited to interferon alfa-based therapies with its poor efficacy to side effects ratio. Several novel therapies have now advanced... (Review)
Review
Treatment options for HDV have been limited to interferon alfa-based therapies with its poor efficacy to side effects ratio. Several novel therapies have now advanced into the clinic. As they each have a different mechanism of action, there is the potential for combination therapy. Here we review how studying the HDV life cycle has led to the development of these novel therapies, the key developments leading to, and the details of, the first combination study of novel anti-HDV therapies, and suggest what additional combinations of novel therapies can be anticipated as we enter this exciting new area of HDV treatments.
Topics: Antiviral Agents; Drug Therapy, Combination; Hepatitis D; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans
PubMed: 35215860
DOI: 10.3390/v14020268 -
Drugs of Today (Barcelona, Spain : 1998) Jul 2021Hepatitis B virus (HBV) and its satellite virus hepatitis D (HDV) are common worldwide hepatotrophic infections responsible for cirrhosis and hepatocellular carcinoma...
Hepatitis B virus (HBV) and its satellite virus hepatitis D (HDV) are common worldwide hepatotrophic infections responsible for cirrhosis and hepatocellular carcinoma (HCC). The more common HBV infection has several therapeutic regimens currently available for suppression of viral replication. However, a regimen leading to an effective sustained functional cure is still not available. In contrast, HDV infection, which causes the most severe form of chronic viral hepatitis and an increased rate of HCC, currently has no Food and Drug Administration (FDA)-approved treatment. Bulevirtide is a novel virion entry inhibitor which blocks the virion's hepatocyte pathway of entry, the hepatic sodium/taurocholate cotransporting polypeptide (NTCP) receptor, and is now a promising therapy for both infections. In July 2020 bulevirtide was authorized for use in the E.U. following a positive opinion by the European Medicines Agency (EMA) for the treatment of chronic HDV infection in HDV RNA-positive adult patients with compensated liver disease. In this paper we have examined the studies that led to this approval as well as studies examining the drug's efficacy in treating HBV.
Topics: Adult; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B virus; Hepatitis Delta Virus; Humans; Liver Neoplasms
PubMed: 34268531
DOI: 10.1358/dot.2021.57.7.3283861 -
Clinics in Liver Disease Nov 2023Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately... (Review)
Review
Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately effective interventions exist to decrease transmission. Counseling on the risk of maternal-to-child transmission, care pathways to decrease transmission, and the implications of HBV and HDV on pregnancy outcomes are the key components of caring for pregnant people living with HBV and HDV.
Topics: Infant; Pregnancy; Female; Humans; Hepatitis B virus; Hepatitis Delta Virus; Hepatitis B; Hepatitis B Surface Antigens; Infectious Disease Transmission, Vertical
PubMed: 37778777
DOI: 10.1016/j.cld.2023.05.007 -
Current Opinion in Virology Jun 2018While chronic infection with the human hepatitis B virus (HBV) and hepatitis delta virus (HDV) inflict major health burdens worldwide, current therapies cannot cure... (Review)
Review
While chronic infection with the human hepatitis B virus (HBV) and hepatitis delta virus (HDV) inflict major health burdens worldwide, current therapies cannot cure patients. One possible novel approach is blocking virus entry to prevent the establishment of infection in naïve hepatocytes. As HBV and HDV use identical viral envelope proteins and the same entry mechanisms, such a strategy would target both viruses. Entry inhibitors (e.g. neutralizing antibodies) have been relegated to the limited role of prophylaxis. However, recent clinical data and infection studies show that new viral entry inhibitors could play a major role in eliminating intrahepatic HBV/HDV genomes. We highlight the consequences on viral persistence after preventing virus entry and the therapeutic benefits entry inhibitors could achieve.
Topics: Animals; Antibodies, Neutralizing; Antiviral Agents; Disease Models, Animal; Hepatitis B; Hepatitis B Antibodies; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Virus Internalization
PubMed: 29775812
DOI: 10.1016/j.coviro.2018.04.004 -
Viruses Jan 2022The hepatitis delta virus (HDV) is the smallest known human virus, yet it causes great harm to patients co-infected with hepatitis B virus (HBV). As a satellite virus of... (Review)
Review
The hepatitis delta virus (HDV) is the smallest known human virus, yet it causes great harm to patients co-infected with hepatitis B virus (HBV). As a satellite virus of HBV, HDV requires the surface antigen of HBV (HBsAg) for sufficient viral packaging and spread. The special circumstance of co-infection, albeit only one partner depends on the other, raises many virological, immunological, and pathophysiological questions. In the last years, breakthroughs were made in understanding the adaptive immune response, in particular, virus-specific CD4+ and CD8+ T cells, in self-limited versus persistent HBV/HDV co-infection. Indeed, the mechanisms of CD8+ T cell failure in persistent HBV/HDV co-infection include viral escape and T cell exhaustion, and mimic those in other persistent human viral infections, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), and HBV mono-infection. However, compared to these larger viruses, the small HDV has perfectly adapted to evade recognition by CD8+ T cells restricted by common human leukocyte antigen (HLA) class I alleles. Furthermore, accelerated progression towards liver cirrhosis in persistent HBV/HDV co-infection was attributed to an increased immune-mediated pathology, either caused by innate pathways initiated by the interferon (IFN) system or triggered by misguided and dysfunctional T cells. These new insights into HDV-specific adaptive immunity will be discussed in this review and put into context with known well-described aspects in HBV, HCV, and HIV infections.
Topics: Adaptive Immunity; Animals; CD8-Positive T-Lymphocytes; Hepatitis D; Hepatitis Delta Virus; Humans; Immune Evasion; Virus Replication
PubMed: 35215790
DOI: 10.3390/v14020198 -
Journal of Dental Research Oct 2023Hepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjögren's disease (SjD) patients in the absence of a hepatitis B virus (HBV)...
Hepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjögren's disease (SjD) patients in the absence of a hepatitis B virus (HBV) coinfection. Previous research has shown that HDV antigen (HDAg) expression can trigger an SjD-like phenotype in vivo, demonstrating a potential cause-and-effect relationship. We hypothesize that if HDV plays a role in the development of SjD, then HDV profiles may be correlated with disease manifestations. This retrospective study characterized HDV in a cohort of 48 SjD MSG samples collected between 2014 and 2021. Analyses of HDAg expression, including cell type and subcellular localization, in situ hybridization of HDV RNA, and comparative analyses with associated SjD and viral hepatitis clinical features, were conducted. HDAg was detected in MSG acinar, ductal, myoepithelial, and adipose cells and localized with the nuclei, cytoplasm, and mitochondria. In situ hybridization detected HDV genomic RNA localization in the MSG nuclei. A significant negative correlation was found between HDAg intensity and focal lymphocytic inflammation and in patients with both anti-SSA/Ro-52 and anti-SSA/Ro-60. In analyzing autoimmune disease comorbidities with SjD, it was found that SjD patients diagnosed with autoimmune thyroiditis and/or hypothyroidism were significantly more represented in the high HDAg intensity group compared to the negative and moderate HDAg intensity groups. No significant associations were detected between MSG-localized HDAg and liver enzymes or an evident HBV coinfection. This study has further confirmed that there is a nonhepatic reservoir for chronic HDV persistence in SjD-affected salivary gland tissue in a third independent SjD patient cohort. In addition, this study describes the unique colocalization of HDAg with mitochondria. The detection of HDV antigen and sequence within SjD-affected salivary gland tissue, and in the absence of an evident current or past HBV coinfection, warrants further investigation.
Topics: Humans; Hepatitis Delta Virus; Hepatitis delta Antigens; Retrospective Studies; Coinfection; Salivary Glands, Minor; Hepatitis B; Hepatitis B virus; Sjogren's Syndrome; RNA
PubMed: 37575047
DOI: 10.1177/00220345231186394 -
Viruses Dec 2022The genomes of RNA viruses may be monopartite or multipartite, and sub-genomic particles such as defective RNAs (D RNAs) or satellite RNAs (satRNAs) can be associated... (Review)
Review
The genomes of RNA viruses may be monopartite or multipartite, and sub-genomic particles such as defective RNAs (D RNAs) or satellite RNAs (satRNAs) can be associated with some of them. D RNAs are small, deletion mutants of a virus that have lost essential functions for independent replication, encapsidation and/or movement. D RNAs are common elements associated with human and animal viruses, and they have been described for numerous plant viruses so far. Over 30 years of studies on D RNAs allow for some general conclusions to be drawn. First, the essential condition for D RNA formation is prolonged passaging of the virus at a high cellular multiplicity of infection (MOI) in one host. Second, recombination plays crucial roles in D RNA formation. Moreover, during virus propagation, D RNAs evolve, and the composition of the particle depends on, e.g., host plant, virus isolate or number of passages. Defective RNAs are often engaged in transient interactions with full-length viruses-they can modulate accumulation, infection dynamics and virulence, and are widely used, i.e., as a tool for research on -acting elements crucial for viral replication. Nevertheless, many questions regarding the generation and role of D RNAs in pathogenesis remain open. In this review, we summarise the knowledge about D RNAs of plant viruses obtained so far.
Topics: Animals; Humans; RNA, Viral; Plant Viruses; RNA Viruses; RNA, Satellite; Virus Replication; Defective Viruses
PubMed: 36560818
DOI: 10.3390/v14122814 -
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 -
Journal of Virology Jun 2021Epstein-Barr virus (EBV) is a human gammaherpesvirus that is causally associated with various lymphomas and carcinomas. Although EBV is not typically associated with...
Epstein-Barr virus (EBV) is a human gammaherpesvirus that is causally associated with various lymphomas and carcinomas. Although EBV is not typically associated with multiple myeloma (MM), it can be found in some B-cell lines derived from MM patients. Here, we analyzed two EBV-positive MM-patient-derived cell lines, IM9 and ARH77, and found defective viral genomes and atypical viral gene expression patterns. We performed transcriptome sequencing to characterize the viral and cellular properties of the two EBV-positive cell lines, compared to the canonical MM cell line 8226. Principal-component analyses indicated that IM9 and ARH77 clustered together and distinct from 8226. Immunological Genome Project analysis designated these cells as stem cell and bone marrow derived. IM9 and ARH77 displayed atypical viral gene expression, including leaky lytic cycle gene expression with an absence of lytic DNA amplification. Genome sequencing revealed that the EBV genomes in ARH77 contain large deletions, while IM9 has copy number losses in multiple EBV loci. Both IM9 and ARH77 showed EBV genome heterogeneity, suggesting cells harboring multiple and variant viral genomes. We identified atypical high-level expression of lytic genes BLRF1 and BLRF2. We demonstrated that short hairpin RNA (shRNA) depletion of BLRF2 altered viral and host gene expression, including a reduction in lytic gene activation and DNA amplification. These findings demonstrate that aberrant viral genomes and lytic gene expression persist in rare B cells derived from MM tumors, and they suggest that EBV may contribute to the etiology of MM. EBV is an oncogenic herpesvirus, but its mechanisms of oncogenesis are not fully understood. A role for EBV in MM has not yet been established. We analyzed EBV-positive B-cell lines derived from MM patients and found that the cells harbored defective viral genomes with aberrant viral gene expression patterns and cell gene signatures for bone marrow-derived lymphoid stem cells. These findings suggest that aberrant EBV latent infection may contribute to the etiology of MM.
Topics: Animals; B-Lymphocytes; Cells, Cultured; DNA Copy Number Variations; Defective Viruses; Disease Models, Animal; Gene Deletion; Gene Expression Regulation, Viral; Genome, Viral; Herpesvirus 4, Human; Humans; Mice; Mice, SCID; Multiple Myeloma; Oxidative Stress; RNA Interference; RNA, Small Interfering; Transcriptome; Virus Activation
PubMed: 33883224
DOI: 10.1128/JVI.00088-21 -
Journal of Virology Jan 2021The recent highly pathogenic avian influenza (HPAI) H5N1 and H7N9 viruses have caused hundreds of human infections with high mortality rates. Although H5N1 and H7N9...
The recent highly pathogenic avian influenza (HPAI) H5N1 and H7N9 viruses have caused hundreds of human infections with high mortality rates. Although H5N1 and H7N9 viruses have been limited mainly to avian species, there is high potential for these viruses to acquire human-to-human transmission and initiate a pandemic. A highly safe and effective vaccine is needed to protect against a potential H5N1 or H7N9 influenza pandemic. Here, we report the generation and evaluation of two reassortant influenza viruses, PR8-H5-H7 and PR8-H7-H5 These viruses contain six internal segments from A/Puerto Rico/8/1934 (PR8), the HA segment from either A/Alberta/01/2014 (H5N1) [AB14 (H5N1)] or A/British Columbia/01/2015 (H7N9) [BC15 (H7N9)], and a chimeric NA segment with either the BC15 (H7N9) HA gene or the AB14 (H5N1) HA gene flanked by the NA packaging signals of PR8. These viruses expressed both H5 and H7 HAs in infected cells, replicated to high titers when exogenous NA was added to the culture medium , and were replication defective and nonvirulent when administered intranasally in mice. Moreover, intranasal vaccination with PR8-H5-H7 elicited robust immune responses to both H5 and H7 viruses, conferring complete protection against both AB14 (H5N1) and BC15 (H7N9) challenges in mice. Conversely, vaccination with PR8-H7-H5 only elicited robust immune responses toward the H7 virus, which conferred complete protection against BC15 (H7N9) but not against AB14 (H5N1) in mice. Therefore, PR8-H5-H7 has strong potential to serve as a vaccine candidate against both H5 and H7 subtypes of influenza viruses. Avian influenza H5N1 and H7N9 viruses infected humans with high mortality rates. A highly safe and effective vaccine is needed to protect against a potential pandemic. We generated and evaluated two reassortant influenza viruses, PR8-H5-H7 and PR8-H7-H5, as vaccine candidates. Each virus contains one type of HA in segment 4 and the other subtype of HA in segment 6, thereby expressing both H5 and H7 subtypes of the HA molecule. The replication of viruses is dependent on the addition of exogenous NA in cell culture and is replication defective Vaccination of PR8-H5-H7 virus confers protection to both H5N1 and H7N9 virus challenge; conversely, vaccination of PR8-H7-H5 provides protection only to H7N9 virus challenge. Our data revealed that when engineering such a virus, the H5 or H7 HA in segment 6 affects the immunogenicity. PR8-H5-H7 has strong potential to serve as a vaccine candidate against both H5 and H7 subtypes of influenza viruses.
Topics: Animals; Dogs; Female; Hemagglutinin Glycoproteins, Influenza Virus; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza Vaccines; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Vaccination; Vaccines, Inactivated; Virus Replication
PubMed: 33177192
DOI: 10.1128/JVI.02154-20