Elevated LAG-3 on CD4+ T cells negatively correlates with neutralizing antibody response during HCV infection.

Lymphocyte activation gene-3 (LAG-3), an inhibitory molecule, which has been shown co-expressed with multiple inhibitory receptors on CD8+ T and natural killer (NK) cells and negatively regulates T and NK cell responses during hepatitis C virus (HCV) infection. However, whether LAG-3 is involved in the regulation of the antibody response remains unclear. This study aims to investigate the relationship of LAG-3 with neutralizing antibody (nAb) response during HCV infection. A total of 66 HCV-infected individuals and 36 sex- and age-matched healthy controls from a population of intravenous drug users were recruited. Circulating follicular helper T (cTfh) cells and LAG-3-expressing CD4+ T cells, type 1 regulatory T (Tr1) cells, and regulatory T (Treg) cells were characterized by flow cytometry. Serum nAb response of HCV-infected individuals was determined using pseudoparticle neutralization assays. We found that HCV infection enhanced LAG-3 expression on CD4+ T cells and exhibited regulatory T cell-like phenotype and inversely associated with the HCV nAb response. Further analysis showed that frequency of CXCR3+ cTfh cells positively correlated with nAb response, however LAG-3+ CD4+ T cells inversely associated with CXCR3+ cTfh cells. This study observed that LAG-3+ CD4+ T cells exhibit a regulatory cell phenotype and negatively associate with the HCV nAb response, implying that LAG-3 may be involved in the negative regulation of humoral immunity during HCV infection.

Hepatitis B, C, and D virus infection showing distinct patterns between injection drug users and the general population.

BACKGROUND AND AIM: Hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are known to be prevalent in injection drug users (IDUs); however, the relationship between the molecular epidemiologic features of hepatitis virus infection in high-risk individuals and the general population has not yet been established. METHODS: In total, 1049 IDUs and 672 individuals who underwent physical examinations at Chenzhou hospital, Hunan Province, China, were enrolled. HBV, HCV, and HDV infections were screened with serologic tests in both populations. HBsAg-positive, anti-HCV IgG-positive, and anti-HDV IgG-positive samples were further confirmed by polymerase chain reaction, quantitative polymerase chain reaction, and DNA sequencing. RESULTS: Significantly higher HBV (21.54 vs 16.52%, P = 0.01), HCV (45.95% vs 1.34%, P < 0.001), and HDV (5.62% vs 0.30%, P < 0.001) infections were detected in IDUs compared with the general population. The dual infection of HBV/HCV or HBV/HDV was also significantly higher in IDUs than in the general population. HBV genotype B and HDV genotype II were dominants in both populations. HCV infection showed genotype 6a (49.52%) dominant in IDUs, but genotype 1b accounted for 50% infection, which was followed by genotype 6a (33.33%) in the general population. Higher viral loads were associated with HBV genotype B and HCV genotype 6a compared with non-dominant genotypic infections. CONCLUSIONS: HBV and HDV infections shared similar patterns by IDUs and the general populations, and HCV infection exhibited distinct features between two populations. Our results suggest different molecular epidemiologic characteristics of HBV, HCV, and HDV infection in two populations.

HBV/HCV dual infection impacts viral load, antibody response, and cytokine expression differently from HBV or HCV single infection.

Hepatitis B virus/hepatitis C virus (HBV/HCV) dual infection is common among high-risk individuals. To characterize the virological and immunological features of patients with HBV/HCV dual infection, we enrolled 1,049 individuals who have been identified as injection drug users. Patients were divided into single and dual infection groups according to the serological markers. We found the average HCV RNA level was significantly lower; however, HBV viral load was significantly higher in HBV/HCV dual-infected patients (n = 42) comparing HCV single infection (n = 340) or HBV single infection (n = 136). The level of anti-HBs in patients who experienced spontaneous HBV clearance was higher than that in HCV single-infected patients with HBV spontaneous clearance. The level of anti-HCV E2 in HBV/HCV dual infection was lower than that detected in HCV single infection. Serum levels of IL-6, IL-8, and TNF-α were significantly lower in HBV/HCV dual-infected patients than in patients infected with HBV or HCV alone. Taken together, two viral replications are imbalanced in dual infected patients. The anti-HBs and anti-HCV E2 antibody production were impaired and proinflammatory IL-6, IL-8, and TNF-α also downregulated due to dual infection. These findings will help further understanding the pathogenesis of HBV/HCV dual infection.