• Bioengineering
• Cancer-cell derived EV
• Extracellular Vesicles
• Immune escape
• Viral EV

• Cancer regulation
• Cancer treatment
• Interferons

• Humans
• Neoplasms/drug therapy
• Neoplasms/virology
• Neoplasms/immunology
• Interferons/therapeutic use
• Interferons/metabolism
• Signal Transduction/drug effects
• Animals
• Antiviral Agents/therapeutic use
• Antiviral Agents/pharmacology
• Virus Diseases/drug therapy
• Virus Diseases/immunology

• cohort studies
• colorectal cancer
• hepatitis C virus
• meta-analysis
• systematic review

• HCV
• drug resistance
• genotype
• hepatology
• prevention
• viral hepatitis
• virology

• EBV
• HBV
• HCV
• HIV
• lymphoma
• pathogenesis
• virus

• Humans
• Lymphoma/etiology
• Oncogenic Viruses
• Herpesvirus 8, Human

• Department of Science and Technology of Jilin Province

• Breast cancer
• Endorphin
• Stress
• Telomeres

• Animals
• Female
• Humans
• beta-Endorphin/metabolism
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cognitive Behavioral Therapy
• Depression/metabolism
• Endorphins/metabolism
• Receptors, Opioid/metabolism
• Signal Transduction
• Stress, Psychological/metabolism

• HBV
• HCC
• HCV
• cargo
• exosomes
• fibrosis
• immune response
• immunosuppression
• quasi-enveloped
• viral hepatitis

The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.

• KAI1/CD82
• Autotaxin
• Lysophosphatidic acid
• Pancreatic cancer
• Liver cancer

• CD8(+) T cell
• Direct Acting Antivirals (DAAs)
• HCV
• HLA-E
• NK cell
• NKG2A
• Polymorphism
• Thalassemia
• Transfusion

• Alleles
• Antiviral Agents/therapeutic use
• Blood Transfusion
• Hepacivirus
• Hepatitis C/drug therapy
• Hepatitis C/genetics
• Hepatitis C/immunology
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/genetics
• Hepatitis C, Chronic/immunology
• Histocompatibility Antigens Class I/genetics
• Histocompatibility Antigens Class I/immunology
• Humans
• Thalassemia/drug therapy
• Thalassemia/genetics
• Thalassemia/immunology
• Thalassemia/therapy
• HLA-E Antigens

• hepatitis C virus
• modified E2
• proinflammatory response
• vaccine antigen
• vaccine antigen selection

Hepatitis C virus (HCV) is a small positive-sense, single-stranded RNA virus, the causal organism for chronic hepatitis. Chronic hepatitis leads to inflammation of liver, causing cirrhosis, fibrosis and steatosis, which may ultimately lead to liver cancer in a few cases. Innate and adaptive immune responses play an important role in the pathogenesis of HCV infection, thus acting as an important component in deciding the fate of the disease. Numerous studies have indicated that the derangement of these immune responses results in the persistence of infection leading to chronic state of the disease. Interactions between virus and host immune system generally result in the elimination of virus, but as the virus evolves with different evading mechanisms, it makes environment favourable for its survival and replication. It has been reported that HCV impairs the immune system by functional modulation of the cells of innate as well as adaptive immune responses, resulting in chronic state of the disease, influencing the response to antiviral therapy in these patients. These defects in the immune system lead to suboptimal immune responses and therefore, impaired effector functions. This review highlights the involvement or association of different immune cells such as natural killer cells, B cells, dendritic cells and T cells in HCV infection and how the virus plays a role in manipulating certain regulatory mechanisms to make these cells dysfunctional for its own persistence and survival.

• B cell
• T cell
• chronic hepatitis C
• dendritic cell
• immune response
• natural killer cell
• survival

• biomarker
• chronic liver disease
• extracellular vesicles
• hepatic fibrosis
• therapy

• Cytokines
• Hepatitis C virus
• IL-1
• IL-6
• Serum amyloid A
• TNF-α

• DNAM-1
• NK cells
• Nectin-2
• PVR
• activating ligands
• immune surveillance
• viral life cycle phases
• viruses

• Hepatitis C virus
• KIR
• NK cells
• interferon-γ

Natural killer (NK) cells are implicated as important anti-viral immune effectors in varicella zoster virus (VZV) infection. VZV can productively infect human NK cells, yet it is unknown how, or if, VZV can directly affect NK cell function. Here we demonstrate that VZV potently impairs the ability of NK cells to respond to target cell stimulation in vitro, leading to a loss of both cytotoxic and cytokine responses. Remarkably, not only were VZV infected NK cells affected, but VZV antigen negative NK cells that were exposed to virus in culture were also inhibited. This powerful impairment of function was dependent on direct contact between NK cells and VZV infected inoculum cells. Profiling of the NK cell surface receptor phenotype by multiparameter flow cytometry revealed that functional receptor expression is predominantly stable. Furthermore, inhibited NK cells were still capable of releasing cytotoxic granules when the stimulation signal bypassed receptor/ligand interactions and early signalling, suggesting that VZV paralyses NK cells from responding. Phosflow examination of key components in the degranulation signalling cascade also demonstrated perturbation following culture with VZV. In addition to inhibiting degranulation, IFN-γ and TNF production were also repressed by VZV co-culture, which was most strongly regulated in VZV infected NK cells. Interestingly, the closely related virus, herpes simplex virus type 1 (HSV-1), was also capable of efficiently infecting NK cells in a cell-associated manner, and demonstrated a similar capacity to render NK cells unresponsive to target cell stimulation–however HSV-1 differentially targeted cytokine production compared to VZV. Our findings progress a growing understanding of pathogen inhibition of NK cell function, and reveal a previously unreported strategy for VZV to manipulate the immune response.

Natural killer (NK) cells–as their name implies–are the immune system’s ready to respond ‘killers’, being able to help control viral infection by cytolytic killing of infected cells and secretion of pro-inflammatory cytokines to activate and direct the immune response. In retaliation, viruses like varicella zoster virus (VZV; the cause of chickenpox and shingles) work to dampen the immune system in order to establish infection in human hosts. We have identified a previously uncharacterised ability of VZV to render NK cells unresponsive to target cells, hindering NK cells from both cytotoxic function and cytokine production. NK cells still maintained predominantly stable expression of functional surface receptors, and were capable of releasing cytotoxic granules when given a receptor-independent stimulus. In this way, VZV paralyses NK cells from functionally responding to target cells, essentially taking the ‘killer’ out of natural killer cells.

• Animals
• Chlorocebus aethiops
• Herpes Simplex/immunology
• Herpes Simplex/pathology
• Herpesvirus 1, Human/immunology
• Herpesvirus 3, Human/immunology
• Humans
• Interferon-gamma/immunology
• Killer Cells, Natural/immunology
• Killer Cells, Natural/pathology
• Signal Transduction/immunology
• Tumor Necrosis Factor-alpha/immunology
• Varicella Zoster Virus Infection/immunology
• Vero Cells

• National Health and Medical Research Council

Hepatitis C virus (HCV) persistently infects approximately 71 million people globally. To prevent infection a vaccine which elicits neutralizing antibodies against the virus envelope proteins (E1/E2) which are required for entry into host cells is desirable. DNA vaccines are cost-effective to manufacture globally and despite recent landmark studies highlighting the therapeutic efficacy of DNA vaccines in humans against cervical cancer, DNA vaccines encoding E1/E2 developed thus far are poorly immunogenic. We now report a novel and highly immunogenic DNA vaccination strategy that incorporates secreted E1 and E2 (sE1 and sE2) into oligomers by fusion with the oligomerization domain of the C4b-binding protein, IMX313P. The FDA approved plasmid, pVax, was used to encode sE1, sE2, or sE1E2 with or without IMX313P, and intradermal prime-boost vaccination studies in BALB/c mice showed that vaccines encoding IMX313P were the most effective in eliciting humoral and cell-mediated immunity against the envelope proteins. Further boosting with recombinant E1E2 proteins but not DNA nor virus-like particles (VLPs) expressing E1E2 increased the immunogenicity of the DNA prime-boost regimen. Nevertheless, the antibodies generated by the homologous DNA prime-boost vaccinations more effectively inhibited the binding of VLPs to target cells and neutralized transduction with HCV pseudoparticles (HCVpp) derived from different genotypes including genotypes 1, 2, 3, 4, 5, and 6. This report provides the first evidence that IMX313P can be used as an adjuvant for E1/E2-based DNA vaccines and represents a translatable approach for the development of a HCV DNA vaccine.

• DNA vaccine
• HCV envelope proteins
• IMX313P
• hepatitis C vaccine
• immune response
• liver disease
• preventative vaccination
• viral hepatitis

• hepatitis c virus
• e2 envelope glycoprotein
• antigen presenting cells
• transcription factors
• immunity

Exhaustion of cytotoxic effector natural killer (NK) and CD8⁺ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/O^Tg mice permissive for persistent HCV infection, that NK and CD8⁺ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8⁺ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8⁺ T cell functions to prevent persistent HCV infection.

Immune cells may become less responsive, or ‘exhausted’, upon chronic viral infection, but the underlying mechanism and crosstalk are still unclear. Here the authors show that, upon chronic hepatitis C virus (HCV) infection, natural killer cell exhaustion is induced by NKG2A signalling to instruct downstream exhaustion of CD8⁺ T cells and HCV persistence.

• NK cell
• complement
• cytokine
• hepatitis C virus
• innate immunity
• interferon

• Hepacivirus/immunology
• Host-Pathogen Interactions/immunology
• Humans
• Immunity, Innate
• Inflammation/pathology
• Interferons/biosynthesis
• Killer Cells, Natural/immunology

• R01 DK081817 NIDDK NIH HHS
• R01 DK113645 NIDDK NIH HHS

• Cytotoxicity
• Hepatitis C
• IFN-gamma
• NK cells
• PD-1

• FACS analysis
• chronic HCV paediatric patients
• lymphocytes

Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.

• direct-acting antiviral agents
• fibrogenesis
• hepatitis C virus
• hepatocellular carcinoma
• interferon
• reactive oxygen species
• recurrence
• sustained virological response

Natural killer cells (NK cells) play an essential role in the immunological mechanism underlying chronic hepatitis C (CHC). Impairment of NK cell function facilitates persistent infection with hepatitis C virus (HCV) and hepatocellular carcinogenesis. However, the mechanism by which NK cell activity is suppressed in CHC is not completely understood. In this study, we focused on carcinoembryonic antigen–related cell‐adhesion molecule 1 (CEACAM1). CEACAM1 is thought to suppress NK cell function. We examined the effect of CEACAM1 on NK cell function in CHC. We investigated the function of CEACAM1 in vitro using Huh7.5.1 cells and the HCV‐Japanese fulminant hepatitis (JFH)‐1 strain. We analyzed serum CEACAM1 level, NK cell function, and CEACAM1 messenger RNA (mRNA) level in human liver samples. Levels of CEACAM1 on the cell surface, CEACAM1 mRNA levels, and soluble CEACAM1 levels in supernatants were significantly higher in Huh7.5.1 cells infected with JFH‐1 (Huh7.5.1/JFH‐1 cells) than in Huh7.5.1 cells. Significantly higher NK cell cytotoxicity was observed toward K562 cells after coculture with CEACAM1 knockout Huh7.5.1/JFH‐1 cells than after coculture with Huh7.5.1/JFH‐1 cells. CEACAM1 expression was induced by the HCV E2 glycoprotein in HCV infection. Significantly higher serum CEACAM1 levels were detected in patients with CHC compared with healthy subjects and patients who achieved sustained virological responses. The expression of CD107a on NK cells from patients with CHC was negatively correlated with serum CEACAM1 levels. Significantly higher levels of CEACAM1 mRNA were detected in HCV‐infected livers compared with uninfected livers. Conclusion: CEACAM1 expression was induced in hepatocytes following HCV infection and decreased NK cell cytotoxicity. These results demonstrate a possible role for CEACAM1 in the pathogenesis of CHC and hepatocellular carcinoma progression.

CD100, also known as Sema4D, is an immune semaphorin constitutively expressed on natural killer (NK) cells and T cells. As an immune activation molecule, CD100 has important immunoregulatory effects on NK functions by enhancing the interactions between NK cells and target cells. The aim of this study was to investigate whether hepatitis C virus (HCV) infection affects CD100 expression, and whether interferon-α treatment enhances NK killing activity to facilitate HCV clearance via CD100.

Expression of CD100 on NK cells was evaluated by flow cytometry in patients with chronic HCV infection, with or without pegylated interferon-α-based therapy. NK cell cytotoxicity and interferon (IFN)-γ production were measured by flow cytometry upon culturing the NK cells with K562 and Huh7.5 or HCV JFH-1-infected Huh7.5 cells.

The frequency of CD100⁺ NK cells in HCV-infected individuals was slightly suppressed compared to healthy subjects. IFN-α treatment could significantly upregulate CD100 expression, which was confirmed by in vitro studies using peripheral blood mononuclear cells cocultured with HCV-expressing Huh7.5 cells or IFN-α. Importantly, the expression of CD100 on NK cells from HCV patients was inversely associated with the HCV-RNA levels in the early phase of IFN-α therapy, and the IFN-α upregulated CD100 led to an enhanced NK killing activity through ligations with its receptors plexin-B1/B2 on target cells.

These results implied a novel mechanism by which IFN-α enhanced CD100/Plexin-B1/B2 interaction plays an important role in promoting NK functions in patients with chronic hepatitis C.

• CD100
• hepatitis C virus
• interferon-α
• natural killer cells
• plexin-B1/B2

• HCV viral load
• HIV/HCV
• T cells
• hepatitis C virus
• natural killer

• HCV
• Hepatitis
• Host-pathogen interaction
• Immune evasion
• Immunogenetics
• Infection

• HCC
• HCV
• IFN-γ
• sFASL
• sFGL2

The high seroprevalence of human herpesvirus type 8 (HHV-8) in moderate or severe cirrhotics appears to be associated with male sex, hepatitis B virus (HBV) infection, alcoholism, and disease severity. The status of HHV-8 infection in mild cirrhotics remains unclear. Plasma samples collected from 93 mild cirrhotics and 93 age- and sex-matched healthy controls were analyzed for HHV-8 antibody and HHV-8 DNA. Mild cirrhotics had higher seropositivity for HHV-8 antibodies than healthy controls (P=0.0001). Univariate logistic regression analysis revealed that an age ≥55 years (odds ratio (OR) 2.88, P=0.02), hepatitis C virus (HCV) infection (OR 3.42, P=0.01), and hepatitis activity (OR 4.10, P=0.004) were associated with HHV-8 seropositivity in cirrhotics. Stepwise multivariate logistic regression analysis confirmed that age ≥55 years (adjusted OR (aOR) 1.92, P=0.04) and hepatitis activity (aOR 3.55, P=0.005) were independent factors. The rate of hepatitis activity was higher in HCV-infected than in HBV-infected patients (P<0.0001) and in women than in men (P=0.0001). Cirrhotics who were seropositive for HHV-8 or HCV or had hepatitis activity were significantly older (P=0.02, <0.0001 and <0.0001, respectively). Plasma samples from all participants were negative for HHV-8 DNA. HHV-8 antibody titers in mild cirrhotics also markedly exceeded those in controls (P<0.0001), as did those in patients ≥55 years old vs. younger patients (P=0.01), those in patients with vs. without HCV infection (P=0.0008), and those in patients with vs. without hepatitis activity (P=0.0005). Mild cirrhotics had high HHV-8 seroprevalence and HCV infection, and, in particular, old age and hepatitis activity were predictors.

• NS5A
• Vitamin D
• chronic hepatitis C
• resistance-associated variants

• avian influenza virus (AIV)
• cytotoxicity
• direction infection
• immunoevasion
• inhibition
• natural killer (NK) cell

Interferon alpha is a widely used therapeutic agent in the treatment of hepatitis C virus infection. Clinical thyroid disease is seen in nearly 15 % of patients receiving interferon alpha for hepatitis C virus infection. The mechanism of thyroid dysfunction with interferon alpha is either autoimmune or inflammatory. We report a case of young woman who developed biphasic thyroid dysfunction posing a diagnostic challenge, while receiving interferon alpha treatment for hepatitis C virus infection.

A 29-year-old, Caucasian woman with type 1 diabetes and hepatitis C virus infection was referred with hyperthyroidism, while she was at 17 weeks of a planned 24-week course of interferon alpha therapy. A laboratory investigation revealed a thyroid stimulation hormone level of 0.005 mU/L (0.350–4.94), free thyroxine of 45.6 pmol/L (9.0–19.0) and free tri-iodothyronine of 12.6 pmol/L (2.6–5.7). She had a mild neutropenia and alanine aminotransferase at double the reference value. Her thyroid peroxidase antibody level was 497 ku/L (<5.6) and thyroid inhibitory factor 7 IU/L (>1.8 iu/l is positive). Thyroid scintigraphy with technetium99 scan confirmed a normal-sized thyroid gland with diffuse but normal overall uptake. A diagnosis of interferon alpha-triggered autoimmune hyperthyroidism as opposed to an inflammatory thyroiditis was made. She was offered radioactive iodine therapy, as thionamides were considered inappropriate in view of her liver disease and mild neutropenia. Due to our patient’s personal circumstances, radioactive iodine therapy was delayed by 8 weeks and her thyrotoxic symptoms were controlled with beta-blockers alone. A repeat thyroid function test, 4 weeks post treatment with interferon alpha, indicated spontaneous conversion to hypothyroidism with a thyroid stimulation hormone level of 100 mU/L, free thyroxine of 5.2 pmol/L and free tri-iodothyronine of 1.7 pmol/L. She subsequently received levothyroxine for 4 months only and had remained euthyroid for the last 3 months without any treatment.

Initial investigations favored the autoimmune nature of hyperthyroidism but follow-up of the case, interestingly, was more consistent with inflammatory thyroiditis. We propose that this can be explained either on the basis of autoimmune subacute thyroiditis or a change in the nature of thyroid stimulation hormone receptor antibody production from stimulating-type to blocking-type antibodies, with disappearance of the latter on discontinuation of interferon alpha.

• Autoimmune
• Hepatitis C virus
• Hyperthyroidism
• Hypothyroidism
• Interferon alpha

• exosome
• microvesicle
• prostate cancer
• tumor microenvironment

• Animals
• Hepatitis B virus/immunology
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/pathology
• Hepatitis B, Chronic/virology
• Humans
• Killer Cells, Natural/immunology

• National Natural Science Foundation of China
• Natural Science Foundation of Chongqing

• Adaptive immunity
• Hepatitis C
• Human
• Innate immunity
• Regulatory T cells

• NK cells
• immunotherapy
• solid tumor
• tumor escape
• tumor microenvironment
• virotherapy

• HIV-1 infection inhibition
• Human embryonic stem cells
• In vitro
• In vivo
• Induced pluripotent stem cells
• Natural killer cells