Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level

Abstract

Background & Aims Hepatitis D virus (HDV) superinfection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, and no vaccine is available. Although HDV-specific CD8 + T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8 + T cells or why these cells ultimately fail to control the infection. We aimed to define how HDV escapes the CD8 + T-cell–mediated response. Methods We collected plasma and DNA samples from 104 patients with chronic HDV and HBV infection at medical centers in Europe and the Middle East, sequenced HDV, typed human leukocyte antigen (HLA) class I alleles from patients, and searched for polymorphisms in HDV RNA associated with specific HLA class I alleles. We predicted epitopes in HDV that would be recognized by CD8 + T cells and corresponded with the identified virus polymorphisms in patients with resolved (n = 12) or chronic (n = 13) HDV infection. Results We identified 21 polymorphisms in HDV that were significantly associated with specific HLA class I alleles ( P < .005). Five of these polymorphisms were found to correspond to epitopes in HDV that are recognized by CD8 + T cells; we confirmed that CD8 + T cells in culture targeted these HDV epitopes. HDV variant peptides were only partially cross-recognized by CD8 + T cells isolated from patients, indicating that the virus had escaped detection by these cells. These newly identified HDV epitopes were restricted by relatively infrequent HLA class I alleles, and they bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were not associated with HDV sequence polymorphisms. Conclusions We analyzed sequences of HDV RNA and HLA class I alleles that present epitope peptides to CD8 + T cells in patients with persistent HDV infection. We identified polymorphisms in the HDV proteome that associate with HLA class I alleles. Some variant peptides in epitopes from HDV were only partially recognized by CD8 + T cells isolated from patients; these could be mutations that allow HDV to escape the immune response, resulting in persistent infection. HDV escape from the immune response was associated with uncommon HLA class I alleles, indicating that HDV evolves, at the population level, to evade recognition by common HLA class I alleles.

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.…”

“…[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.…”

Future treatments for hepatitis delta virus infection

“…22 Some HDV polymorphisms allow to escape detection by lymphocytes CD8 + and to evade from the immune response. 23 These results provide insights into the mechanisms of adaptive immunity against HDV; however, more research is needed to fully clarify and understand the interaction of HDV with the immune system. It is interesting to note that HBsAg declined by more than 1 log 10 IU/mL in 47% (7/15) Treatment was well tolerated with mild to moderate drug-related adverse events mainly caused by an increase in total bile acids.…”

Antigenic evolution on global scale reveals potential natural selection of SARS-CoV-2 by pre-existing cross-reactive T cell immunity

“…Moreover, HLA could present the T-cell epitope to the surface of the antigen presenting cell (APC), and further, binding with the T-cell receptors (TCRs) to trigger the immune response 13 . The long-term symbiosis of virus and its host will lead to HLA mediated cellular immunity and accelerate the evolution of virus in multiple cases such as human immunodeficiency virus (HIV) and hepatitis D virus (HDV) 14,15 . Although SARS-CoV-2 is a new emerging pathogen, seasonal HCoVs had been circulating in community for a long time.…”