Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.

Background & Aims: Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system.

Methods: To leverage this opportunity, we used plate-based single-cell RNA-seq to deeply profile myeloid cells from liver fine needle aspirates in patients with HCV before and after DAA treatment.

Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen infection.

Background & Aims: With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. A better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T cell responses in patients with different degrees of viral control.

Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C.

Invariant NK T (iNKT) cells are implicated in viral clearance; however, their role in hepatitis C virus (HCV) infection remains controversial. Here, iNKT cells were studied during different stages of HCV infection. iNKT cells from patients with acute HCV infection and people who inject drugs (PWID) with chronic or spontaneously resolved HCV infection were characterized by flow cytometry.

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 T cells in human hepatitis C virus (HCV) infection before and after treatment.

Hepatitis C virus-specific CD4+ T cell phenotype and function in different infection outcomes.

CD4+ T cell failure is a hallmark of chronic hepatitis C virus (HCV) infection. However, the mechanisms underlying the impairment and loss of virus-specific CD4+ T cells in persisting HCV infection remain unclear. Here we examined HCV-specific CD4+ T cells longitudinally during acute infection with different infection outcomes.

Fc Glycan-Mediated Regulation of Placental Antibody Transfer.

Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta.

Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection.

Objective: Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible.

Fine-mapping of genetic loci driving spontaneous clearance of hepatitis C virus infection.

Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries.

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8 T Cells in Chronic versus Acute Infection.

Distinct molecular pathways govern the differentiation of CD8 effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8 T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4 T cell populations.

Underascertainment of acute hepatitis C virus infections in the U.S. surveillance system: a case series and chart review.

Background: In 2010, the incidence of hepatitis C virus (HCV) infection in the United States was estimated to be 17 000 cases annually, based on 850 acute HCV cases reported to the Centers for Disease Control and Prevention by local public health authorities. Absence of symptomatic disease and lack of a specific laboratory test for acute infection complicates diagnosis and surveillance.

Objective: To validate estimates of the incidence of acute HCV infection by determining the reporting rate of clinical diagnoses of acute infection to the Massachusetts Department of Public Health (MDPH) and Centers for Disease Control and Prevention.

Chronic HCV infection affects the NK cell phenotype in the blood more than in the liver.

Although epidemiological and functional studies have implicated NK cells in protection and early clearance of HCV, the mechanism by which they may contribute to viral control is poorly understood, particularly at the site of infection, the liver. We hypothesized that a unique immunophenotypic/functional NK cell signature exists in the liver that may provide insights into the contribution of NK cells to viral control. Intrahepatic and blood NK cells were profiled from chronically infected HCV-positive and HCV-negative individuals.

Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors.

Background & Aims: There is an unclear relationship between inhibitory receptor expression on T cells and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is often not the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver T cells from patients with hepatitis C virus (HCV) and other viral infections.

Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence.

Vigorous proliferative CD4(+) T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4(+) T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers.

Optimizing the tracking of falls in studies of older participants: comparison of quarterly telephone recall with monthly falls calendars in the MOBILIZE Boston Study.

Tracking falls among elders is challenging. In this reliability study, which took place between October 2007 and February 2008, the authors compared participants' daily recordings of falls on calendars with a telephone survey of recall of falls over the previous 3 months within the population-based MOBILIZE Boston Study cohort, a cohort of 765 elders. From the cohort, 218 participants were randomly selected.

Maximizing clinical research participation in vulnerable older persons: identification of barriers and motivators.

Objectives: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention.

Design: Quantitative and qualitative survey.

Setting: Academic primary care medicine and pre-anesthesia testing clinics.