Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection

Abstract

Background & Aim: Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the anti-virus immune response and liver disease pathogenesis. Methods: We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8 + T-cell epitopes and characterized HDV-specific CD8 + T cells. We associated these with HDV sequence variations and clinical features of patients. Results: We identified 6 CD8 + T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8 + T cells were as frequent as HBV-specific CD8 + T cells, but less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus.

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

“…Our results contradict recent publications suggesting a role for HDV-specific CD8+ T cells in HDV-induced liver pathology. 13,14 Kefalakes et al showed a very weak positive correlation between AST levels and activated HDV-specific CD8+ T cells in circulation in a small number of chronically HDV-infected patients. However, circulating T cells might not reflect what is happening in the liver, and the cytolytic capacity of these cells has yet to be characterized.…”

“…Our results are in accordance with the weak adaptive immune response against HDV antigens and the dysfunctionality of innate immune cells (such as NK and MAIT cells) that has been observed in HDV-infected patients. [10][11][12][13][14] It is known for some individuals that a strong innate immune response against a viral infection can lead to tissue damage and chronic disease rather than to viral clearance, as in the case of HCV. [31][32][33] The transcriptomic analysis of the liver in our model revealed a strong induction of pathways activated by IFN-c and TNF-a in AAV-HBV/HDV-in comparison to AAV-HBV-treated animals.…”

“…[10][11][12] Interestingly, circulating NK cells have an immunoregulatory rather than cytolytic phenotype, and MAIT cells are functionally impaired. 11,12 Very recently, work by Kefalakes et al 13 and Karimzadeh et al 14 showed a weak but positive correlation between the ex vivo frequency of activated HDVspecific CD8+T cells and liver inflammation, suggesting that cellular responses against the virus might indeed be involved in HDV-mediated liver damage. 13,14 However, there are a number of clinical studies showing that HDV-specific T cell response is very weak or undetectable [15][16][17][18] and that there is no correlation between the magnitude of the T cell response and clinical outcomes.…”

“…11,12 Very recently, work by Kefalakes et al 13 and Karimzadeh et al 14 showed a weak but positive correlation between the ex vivo frequency of activated HDVspecific CD8+T cells and liver inflammation, suggesting that cellular responses against the virus might indeed be involved in HDV-mediated liver damage. 13,14 However, there are a number of clinical studies showing that HDV-specific T cell response is very weak or undetectable [15][16][17][18] and that there is no correlation between the magnitude of the T cell response and clinical outcomes. 15,18 Interestingly, the interaction between the infected hepatocytes and the immune cells, as well as the immunologic environment of the liver during HDV infection has not been elucidated, since the models available so farimmunodeficient humanized mice, 19,20 or mice not permissive to HBV coinfection 21 do not completely reproduce the characteristics of the infection as it occurs in humans.…”

TCF-1 regulates the stem-like memory potential of HIV-specific CD8+ T cells in elite controllers

“…In the setting of chronic lymphocytic choriomeningitis (LCMV) infection in mice, TCF-1 marks the subpopulation of stem-like virus-specific CD8+ T cells that is capable of regenerating both the ongoing effector cell response as well as the proliferative burst of effector cells that is observed after blockade of the PD-1 signaling pathway (36)(37)(38). In humans, expression of TCF-1 in subpopulations of virus-specific CD8+ T cells has been reported in individuals chronically 6 infected with hepatitis B virus (HBV) (39), hepatitis D virus (HDV) (40), or Epstein-Barr virus (EBV) (40), and TCF-1 expression has been correlated with virus-specific T cell expansion capacity in the context of infection with hepatitis C virus (HCV) (37,41). Furthermore, in several recent clinical trials of individuals with melanoma, the size of the TCF-1-expressing subpopulation of intra-tumoral CD8+ T cells was strongly correlated with the clinical response to checkpoint blockade therapy (42,43).…”