Lack of TGF-ß production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection.

BACKGROUND & AIMS: Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGF-ß) predict the outcome of acute HCV coinfection, independently of the IL-28B gene polymorphism. METHODS: Intracellular cytokine staining assays against HCV-core, E1, NS2, and NS4 overlapping peptides were used for the analysis of peripheral HCV-specific TGF-ß-producing T cells. Patients were genotyped for IL-28B polymorphisms. Healthy donors' samples were tested as controls. Twenty-four acute hepatitis C-HIV+ patients were followed-up for 15 months defining two groups: (A) Recovered (n=16, 5 spontaneous recoveries, 11 sustained virologic response after treatment), (B) Chronic HCV (n=8, 4 spontaneous chronic course, 4 therapeutic failures). RESULTS: During the acute pretreatment phase, core/NS2-specific TGF-ß-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGF-ß+ cells was characteristic of healthy donors and Group A, except for 2 cases, with frequencies significantly lower than in Group B (p=0.04 and 0.01), and was associated with recovery in 14/16 cases. Presence of anti-HCV TGF-ß+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGF-ß production was independent of the rs129679860 SNP (p=1.0) which was not associated with recovery (p=1.0). CONCLUSIONS: During acute hepatitis C, pre-therapeutic HCV-specific TGF-ß-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.

Acute hepatitis C in HIV-infected patients: rare spontaneous clearance correlates with weak memory CD4 T-cell responses to hepatitis C virus.

OBJECTIVES: To explore the parameters of specific immunity to hepatitis C virus (HCV) associated with virus clearance during acute HCV infection in HIV coinfection. METHODS: HIV-infected patients without prior HCV infection were prospectively enrolled for acute hepatitis C and followed up over 15 months. HCV-specific T cells were assessed by proliferation, ELISpot, intracellular cytokine staining and pentamer assays. Pegylated-interferon-alpha and ribavirin were proposed if HCV persisted at M3. RESULTS: Thirty eight acutely HCV-infected HIV-positive patients were enrolled. HCV genotypes were predominantly 4 and 1. Five patients (13%) showed spontaneous clearance and 20 initiated treatment, of whom 13 (65%) showed sustained virologic responses. Before M3, HCV-specific proliferative responses observed in 35% cases, were associated with lower HCV viral load (P = 0.04) and predictive of spontaneous clearance (P = 0.02), particularly anti-NS4 responses (P = 0.03). These HCV-specific proliferative responses were associated with HIV-p24-specific responses (P = 0.002) independently from the HIV stage. Interferon-gamma-producing T cells specific for HCV were detectable ex vivo in 81% cases but at low intensity (<150 spot forming cells/10 peripheral blood mononuclear cells) and were independent of the HCV outcome. Low frequencies of pentamer-positive HCV-specific CD8 cells (0.01-0.05%) detected in nine of 12 patients were mainly effector-memory PD-1-negative T cells. Twelve days of HCV-specific in-vitro culture induced amplification of CD4 T cells coproducing interleukin-2 and interferon-gamma but rarely of CD8 T cells. CONCLUSION: Acute HCV infection in HIV-coinfected patients is characterized by a low rate of spontaneous clearance and weak HCV-specific memory T cells, not strictly related to HIV-induced immune defects, and which correlate with virus clearance.