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Background & Aims: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry., Methods: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed., Results: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10 -50 ) and the MHC locus 6p21.32 (P = 1.15 × 10 -21 ). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10 -07 ). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants., Conclusions: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection., (Copyright © 2019. Published by Elsevier Inc.)

Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Production of interferon (IFN)-γ by natural killer (NK) cells is attenuated during chronic infection with hepatitis C virus (HCV). We investigated whether this is due to intrinsic or extrinsic mechanisms of NK cells., Methods: Peripheral blood mononuclear cells (PBMCs) were collected from patients with chronic HCV infection or uninfected blood donors (controls); NK cells and monocytes were isolated or eliminated. We cultured hepatoma cells that express luciferase-tagged subgenomic HCV replicons (Huh7/HCV replicon cells) or their HCV-negative counterparts (Huh7) with NK cells in the presence or absence of other populations of PBMCs. Antiviral activity, cytotoxicity, and cytokine production were assessed., Results: NK cells produced greater amounts of IFN-γ when PBMC were cocultured with Huh7/HCV replicon cells than with Huh7 cells; NK cells and PBMCs from controls suppressed HCV replication to a greater extent than those from patients with chronic HCV infection. This antiviral effect was predominantly mediated by tumor necrosis factor (TNF)-α and IFN-γ. The antiviral activity of NK cells and their production of IFN-γ were reduced when they were used in coculture alone (rather than with PBMC), or after depletion of CD14(+) monocytes, after knockdown of the inflammasome in monocytes, or after neutralization of interleukin-18, which is regulated by the inflammasome. These findings indicate a role for monocytes in NK cell activation. Compared with control monocytes, monocytes from patients with chronic HCV infection had reduced TNF-α-mediated (direct) and reduced NK cell-mediated (indirect) antiviral effects. Control monocytes increased the antiviral effects of NK cells from patients with chronic HCV infection and their production of IFN-γ., Conclusions: Monocytes sense cells that contain replicating HCV and respond by producing interleukin-18 via the inflammasome and by activating NK cells. Patients with chronic HCV infection have reduced monocyte function, attenuating NK cell IFN-γ-mediated responses., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

As food allergy increases, more research is devoted to its influence on patient and family mental health and quality of life (QoL). This article discusses the effects on parent and child QoL, as well as distress, while appraising the limitations of knowledge given the methods used. Topics include whether QoL and distress are affected compared with other illnesses, assessment of distress and QoL in parents compared with children, concerns about food allergy-related bullying, and the necessity for evidence-based interventions. Suggestions are offered for how to improve QoL and reduce distress on the way to better coping with food allergy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background & Aims: We followed patients with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections., Methods: Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinfection was defined as the detection of a new HCV infection. Protection was assessed based on the magnitude and duration of viremia following reinfection and generation of T-cell and neutralizing antibody (nAb) responses., Results: Reinfection occurred in 11 IDU (50%) who previously spontaneously controlled primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of reinfected patients. The duration and maximum level of viremia during subsequent episodes of reinfection were significantly decreased compared with those of the primary infection in the same subjects. In contrast to chronic infection, reinfection was associated with a significant increase in the breadth of T-cell responses. During acute infection, nAbs against heterologous viral pseudoparticles were detected in 60% of reinfected subjects; cross-reactive nAbs are rarely detected in patients who progress to chronic infection., Conclusions: HCV reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and generation of cross-reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Despite recent characterization of hepatitis C virus-specific neutralizing antibodies, it is not clear to what extent immune pressure from neutralizing antibodies drives viral sequence evolution in vivo. This lack of understanding is particularly evident in acute infection, the phase when elimination or persistence of viral replication is determined and during which the importance of the humoral immune response has been largely discounted., Methods: We analyzed envelope glycoprotein sequence evolution and neutralization of sequential autologous hepatitis C virus pseudoparticles in 8 individuals throughout acute infection., Results: Amino acid substitutions occurred throughout the envelope genes, primarily within the hypervariable region 1 of E2. When individualized pseudoparticles expressing sequential envelope sequences were used to measure neutralization by autologous sera, antibodies neutralizing earlier sequence variants were detected at earlier time points than antibodies neutralizing later variants, indicating clearance and evolution of viral variants in response to pressure from neutralizing antibodies. To demonstrate the effects of amino acid substitution on neutralization, site-directed mutagenesis of a pseudoparticle envelope sequence revealed amino acid substitutions in hypervariable region 1 that were responsible for a dramatic decrease in neutralization sensitivity over time. In addition, high-titer neutralizing antibodies peaked at the time of viral clearance in all spontaneous resolvers, whereas chronically evolving subjects displayed low-titer or absent neutralizing antibodies throughout early acute infection., Conclusions: These findings indicate that, during acute hepatitis C virus infection in vivo, virus-specific neutralizing antibodies drive sequence evolution and, in some individuals, play a role in determining the outcome of infection.

Background & Aims: Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation., Methods: We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized., Results: HIV-related CD4(+) lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the alpha-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis., Conclusions: Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.