Detection of a Broad Range of Low-Level Major Histocompatibility Complex Class II-Restricted, Hepatitis Delta Virus (HDV)-Specific T-Cell Responses Regardless of Clinical Status.

Background: This study aimed to comprehensively define the breadth and specificity of the hepatitis delta virus (HDV)-specific T-cell response in patients at different stages of chronic coinfection with hepatitis B virus (HBV). Methods: Following in vitro stimulation with an overlapping set of 21 HDV-specific 20mer peptides and exogenous interleukin 2, HDV-specific CD4+ and CD8+ T-cell responses of 32 HDV-infected patients were analyzed by enzyme-linked immunospot analysis and intracellular cytokine staining for interferon γ production at the single-peptide level. Additionally, HLA-binding studies were performed both in silico and in vitro. Results: We were able to detect ≥1 T-cell response in >50% our patients. Interestingly, there was no significant difference between the breadth of the response in patients positive and those negative for HDV by PCR. HDV-specific T-cell responses focused on 3 distinct HDV-specific epitopes that were each detected in 12%-21% of patients-2 HLA class II-restricted epitopes (amino acids 11-30 and 41-60) and 1 major histocompatibility complex class I-restricted epitope (amino acids 191-210). In in vitro HLA-binding assays, the 2 CD4+ T-cell specificities (amino acids 11-30 and 41-60) showed promiscuous binding to multiple HLA-DR molecules. Conclusions: This comprehensive characterization of HDV T-cell epitopes provides important information that will facilitate further studies of HDV immunopathogenesis.

Alcohol-Related Liver Disease Is Rarely Detected at Early Stages Compared With Liver Diseases of Other Etiologies Worldwide.

BACKGROUND & AIMS: Despite recent advances in treatment of viral hepatitis, liver-related mortality is high, possibly owing to the large burden of advanced alcohol-related liver disease (ALD). We investigated whether patients with ALD are initially seen at later stages of disease development than patients with hepatitis C virus (HCV) infection or other etiologies. METHODS: We performed a cross-sectional study of 3453 consecutive patients with either early or advanced liver disease (1699 patients with early and 1754 with advanced liver disease) seen at 17 tertiary care liver or gastrointestinal units worldwide, from August 2015 through March 2017. We collected anthropometric, etiology, and clinical information, as well as and model for end-stage liver disease scores. We used unconditional logistic regression to estimate the odds ratios for evaluation at late stages of the disease progression. RESULTS: Of the patients analyzed, 81% had 1 etiology of liver disease and 17% had 2 etiologies of liver disease. Of patients seen at early stages for a single etiology, 31% had HCV infection, 21% had hepatitis B virus infection, and 17% had nonalcoholic fatty liver disease, whereas only 3.8% had ALD. In contrast, 29% of patients seen for advanced disease had ALD. Patients with ALD were more likely to be seen at specialized centers, with advanced-stage disease, compared with patients with HCV-associated liver disease (odds ratio, 14.1; 95% CI, 10.5-18.9; P < .001). Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. These patients had significantly more visits to health care providers, with more advanced disease, compared with patients without excess alcohol use. The mean model for end-stage liver disease score for patients with advanced ALD (score, 16) was higher than for patients with advanced liver disease not associated with excess alcohol use (score, 13) (P < .01). CONCLUSIONS: In a cross-sectional analysis of patients with liver disease worldwide, we found that patients with ALD are seen with more advanced-stage disease than patients with HCV-associated liver disease. Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. Early detection and referral programs are needed for patients with ALD worldwide.

Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion.

Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5'-NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8(+) T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8(+) T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8(+) T cells negatively correlated with HLA-DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8(+) T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8(+)CD73(+) T cells produce more IL-2 upon HIV-specific and unspecific stimulation than their CD73(-) counterparts and show a higher proliferative capacity. These data indicate that down-regulation of CD73 on CD8(+) T cells correlates with immune activation and leads to functional deficits in HIV infection.