Human hepatitis D virus-specific T cell epitopes

Kohsar, Matin; Landahl, Johanna; Wiesch, Julian Schulze zur

doi:10.1016/j.jhepr.2021.100294

Cited by 3 publications

(5 citation statements)

References 114 publications

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“…Next, we analyzed if amino acid substitutions in the large HDAg are under positive selection in the presence of distinct HLA-molecules. It was previously described that HDV evades from the CD8 + T cell response by selecting mutations in targeted epitopes ( 15 , 17 , 36 , 37 ). These studies utilized cohorts from Europe or North America for analyses of CD8 + T cell responses and the possible consequences of immune escape of HDV.…”

Section: Resultsmentioning

confidence: 99%

“…The selected mutations typically interfere with the interaction of an infected cell with the T cell, either by impairing presentation of the variant epitope or by altering binding of the variant HLA/peptide-complex to the T cell receptor ( 48 ). The full epitope repertoire that is targeted in the L-HDAg in the context of different HLA-types is not well defined yet and epitope mapping was just recently started ( 15 , 17 , 36 , 37 ). Lack of experimental confirmation of novel epitope candidates is an important limitation of this study, however, isolation and storage of PBMCs for functional studies was not possible and would require a much larger effort and more advanced infrastructures.…”

Section: Discussionmentioning

confidence: 99%

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Sequence diversity of hepatitis D virus in Mongolia

et al. 2023

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IntroductionThe Hepatitis Delta Virus (HDV) is a defective, single-stranded RNA virusoid encoding for a single protein, the Hepatitis Delta Antigen (HDAg), which requires the hepatitis B virus (HBV) envelope protein (HBsAg) for its transmission. Currently, hepatitis D is the most aggressive form of viral hepatitis and treatment options are limited. Worldwide 12 million people are chronically infected with HDV being at high risk for progression to cirrhosis and development of liver cancer.ObjectivesAlthough it is well established that Mongolia is the country with the highest prevalence of HDV infections, the information on the molecular epidemiology and factors contributing to HDV sequence diversity are largely unclear. The aim of the study was to characterize the sequence diversity of HDV in rural areas from Mongolia and to determine the extent of HLA class I-associated selection pressure.Patients and methodsFrom the HepMongolia cohort from rural areas in Mongolia, 451 HBsAg-positive individuals were selected and anti-HDV, HDV-RNA and the sequence of the large HDAg was determined. For all individuals the HLA class I locus was genotyped. Residues under selection pressure in the presence of individual HLA class I types were identified with the recently published analysis tool HAMdetector.ResultsOf 431 HBsAg positive patients, 281 were anti-HDV positive (65%), and HDV-RNA could be detected in 207 of 281 (74%) of patients. The complete large HDAg was successfully sequenced from 131 samples. Phylogenetic analysis revealed that all Mongolian HDV isolates belong to genotype 1, however, they separate into several different clusters without clear regional association. In turn, from phylogeny there is strong evidence for recent local transmission events. Importantly, we found multiple residues with strong support for HLA class I-associated selection pressure consistent with a functional CD8+ T cell response directed against HDV.ConclusionHDV isolates from Mongolia are highly diverse. The molecular epidemiology suggests circulation of multiple subtypes and provides evidence for ongoing recent transmissions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sequence diversity of hepatitis D virus in Mongolia

et al. 2023

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“…Also, HDV infection was shown to augment the antiviral state of the hepatocytes, chemokine production, and antigen presentation ( 39 , 40 ). Though the liver damage that results from chronic HDV infection is considered to be primarily mediated by the immune system ( 37 , 41 ), little is known about the role of autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

Non-organ-specific autoantibodies with unspecific patterns are a frequent para-infectious feature of chronic hepatitis D

et al. 2023

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Infections with hepatotropic viruses are associated with various immune phenomena. Hepatitis D virus (HDV) causes the most severe form of viral hepatitis. However, few recent data are available on non-disease-specific and non-organ-specific antibody (NOSA) titers and immunoglobulin G (IgG) levels in chronic hepatitis D (CHD) patients. Here, we examined the NOSA titers and IgG levels of 40 patients with CHD and different disease courses and compared them to 70 patients with chronic hepatitis B (CHB) infection. 43% of CHD patients had previously undergone treatment with pegylated interferon-α (IFN-α). The antibody display of 46 untreated patients diagnosed with autoimmune hepatitis (AIH) was used as a reference. The frequency of elevated NOSA titers (CHD 69% vs. CHB 43%, p < 0.01), and the median IgG levels (CHD 16.9 g/L vs. CHB 12.7 g/L, p < 0.01) were significantly higher in CHD patients than in patients with CHB, and highest in patients with AIH (96%, 19.5 g/L). Also, the antinuclear antibody pattern was homogeneous in many patients with AIH and unspecific in patients with viral hepatitis. Additionally, f-actin autoantibodies were only detectable in patients with AIH (39% of SMA). In CHD patients, IgG levels correlated with higher HDV viral loads, transaminases, and liver stiffness values. IgG levels and NOSA were similar in CHD patients irrespective of a previous IFN-α treatment. In summary, autoantibodies with an unspecific pattern are frequently detected in CHD patients with unclear clinical relevance.

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“…The HDV-specific CD4+ T cell epitope repertoire was, so far, only investigated in two studies using OLP covering HDAg, leading to the identification of 18 different HDAg regions targeted by CD4+ T cells [69,72]. The entire L-HDAg was immunogenic, albeit with an accumulation of CD4+ T cell epitopes in the N-terminal region (for a complete list of fine-mapped epitopes, see review [75]). In both studies, CD4+ T cell responses were weak and only detectable after antigen-specific culture for 6 or 12 days, except for one patient with acute HDV infection who displayed ex vivo detectable CD4+ T cells with strong cytokine production [69,72].…”

Section: Cd4+ T Cell Responsementioning

confidence: 99%

“…In total, 17 different CD8+ T cell epitopes were described. For most of these epitopes, epitope fine-mapping and HLA restriction experiments were performed, while, for a smaller number of epitopes, fine-mapping and HLA restriction were only performed in silico ( [70,[72][73][74]86] and recently reviewed in [75]). Of note, the vast majority of defined HDV-specific CD8+ T cell epitopes are restricted by HLA-B alleles.…”

Section: Cd8+ T Cell Responsementioning

confidence: 99%

Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis during HDV Infection

Oberhardt

Hofmann

Thimme

2022

Viruses

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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.

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Human hepatitis D virus-specific T cell epitopes

Cited by 3 publications

References 114 publications

Sequence diversity of hepatitis D virus in Mongolia

Sequence diversity of hepatitis D virus in Mongolia

Non-organ-specific autoantibodies with unspecific patterns are a frequent para-infectious feature of chronic hepatitis D

Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis during HDV Infection

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