AIM： To assess the associations of human leukocyte antigen （HI_A） class Ⅱ DQB1＊0301 and/or DRB1＊1101 allele with spontaneous hepatitis C virus （HCV） clearance by meta-analysis of individual dataset from all st...AIM： To assess the associations of human leukocyte antigen （HI_A） class Ⅱ DQB1＊0301 and/or DRB1＊1101 allele with spontaneous hepatitis C virus （HCV） clearance by meta-analysis of individual dataset from all studies published till date. METHODS： To clarify the impact of HLA class Ⅱ polymorphisms on viral clearance, we performed a metaanalysis of the published data from 11 studies comparing the frequencies of DQB1＊0301 and DRB1＊1101 alleles in individuals with spontaneous resolution to those with persistent infection. As we identified the heterogeneity between studies, summary statistical data were calculated based on a random-effect model. RESULTS： Meta-analyses yielded summary estimatesodds ratio （OR） of 2.36 [95%CI （1.62, 3.43）, P〈0.00001] and 2.02 [95%CI （1.56, 2.62）, P〈0.00001] for the effects of DQB1＊0301 and DRB1＊1101 alleles on spontaneous clearance of HCV, respectively. CONCLUSION： These results support the hypothesis that specific HLA class Ⅱ alleles might influence the susceptibility or resistance to persistent HCV infection. Both DQB1＊0301 and DRB1＊1101 are protective alleles and present HCV epitopes more effectively to CD4^＋T lymphocytes than others, and subjects with these two alleles are at a lower risk of developing chronic HCV infection. Large, multi-ethnic confirmatory and welldesigned studies are needed to determine the host genetic determinants of HCV infection.展开更多
AIM: To further investigate the role of human B7 homolog 1 (B7-H1) in the mechanism of persistent hepatitis B virus (HBV) infection. METHODS: Peripheral and intra-hepatic B7-H1 expression were compared by flow cytomet...AIM: To further investigate the role of human B7 homolog 1 (B7-H1) in the mechanism of persistent hepatitis B virus (HBV) infection. METHODS: Peripheral and intra-hepatic B7-H1 expression were compared by flow cytometry and immunochemical staining between two 2 distinct groups, one being chronic HBV tolerance patients (CHB-T) and the other being acute hepatitis B patients (AHB). B7-H1 mRNA expression level was also compared by real time polymerase chain reaction between CHB-T and AHB patients. The location of intra-hepatic B7-H1 and CD40 expression were analyzed by immunofluorescence. The levels of B7-H1 and CD40 expression on cultured myeloid dendritic cells (mDCs) with or without hepatitis B surface antigen (HBsAg) treatment were analyzed dynamically by flow cytometry. Intracellular interferon-γ (IFN-γ) staining and the stimulatory capacity of mDC of cultured mDC with or without HBsAg treatment were also compared by flow cytometry. RESULTS: Peripheral B7-H1 expression on mDCs was increased significantly in AHB compared to CHB-T patients (P < 0.05). In the liver tissues from CHB-T patients, B7-H1 positive cells were almost absent despite a persistently elevated serum HBsAg load. In contrast, there were indeed increased B7-H1-positive cells in situ in the liver tissue from AHB. In vitro analysis showed the parallel upregulation of B7-H1 and CD40 on CD11c+ mDCs after the onset of stimulation. Addition of recombinant hepatitis B surface antigen (rHBsAg) significantly decreased CD40 expression (P < 0.05 at 16 h, 20 h and 24 h time points). B7-H1 expression was also inhibited by rHBsAg, and the inhibition rate of CD40 was greater than that of B7-H1. This preferential inhibition of CD40 expression on mDCs by rHBsAg resulted in the dysfunction of mDCs and T cells in the mixed leucocyte reaction (MLR) system. With rHBsAg pretreatment, in a carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled MLR system at a ratio of 1:5 responder cell-stimulator cell (R/S), the CFSE dim percentage of T cells decreased from 85.1% to 25.4% and decreased from 30.3% to 12.0% at 1:10 R/S. IFN-γ production by CD8+ T cells, in the MLR system, was reduced significantly by HBsAg pretreatment. At ratios of 1:5 R/S, the percentage of IFN-γ and CD8 dual positive T cells decreased from 55.2% ± 5.3% to 15.1% ±3.1% (P < 0.001), and decreased from 35.0% ± 5.1% to 7.3% ± 2.7% at ratios of 1:10 R/S (P < 0.001). CONCLUSION: B7-H1 is not a signature of immune dysfunction, but an inflammation marker. HBsAg regulate immune response by tipping the balance between B7-H1 and CD40.展开更多
This review analyses current data concerning co-infection with hepatitis C virus(HCV) and human T lymphotropic virus(HTLV)-1/2 in people who inject drugs(PWID), with a particular focus on disease burden and global imp...This review analyses current data concerning co-infection with hepatitis C virus(HCV) and human T lymphotropic virus(HTLV)-1/2 in people who inject drugs(PWID), with a particular focus on disease burden and global implications for virological outcome. In addition, the available treatment options for HTLV-1/2 are summarized and the on-going and likely future research challenges are discussed. The data in this review was obtained from 34 articles on HCV/HTLV-1/2 co-infection in PWID retrieved from the Pub Med literature database and published between 1997 and 2015. Despite unavailable estimates of the burden of HCV/HTLV-1/2 co-infection in general, the epidemiologic constellation of HTLV-1/2 shows high incidence in PWID with history of migration, incarceration, and other blood-borne infectious diseases such as HCV or human immunodeficiency virus. The most recent research data strongly suggest that HTLV-1 co-infection can influence HCV viral load, HCV sustained virological response to α-interferon treatment, and HCV-related liver disease progression. In short, outcome of HCV infection is worse in the context of HTLV-1 co-infection, yet more studies are needed to gain accurate estimations of the burden of HCV/HTLV-1/2 co-infections. Moreover, in the current era of new direct-acting antiviral treatments for HCV and proven HTLV-1/2 treatment options, prospective clinical and treatment studies should be carried out, with particular focus on the PWID patient population, with the aim of improving virological outcomes.展开更多
Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epit...Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.展开更多
Liver disease has recently been described as an im-portant cause of morbidity and mortality in patientsinfected with human immunodeficiency virus （HIV）.Liver test changes are useful surrogates of the burdenof liver ...Liver disease has recently been described as an im-portant cause of morbidity and mortality in patientsinfected with human immunodeficiency virus （HIV）.Liver test changes are useful surrogates of the burdenof liver disease. Previous studies have shown that trans-aminase elevations are frequent among these patients.The cause of those changes is harder to establish inHIV-patients. We present a 61-year-old caucasian male,diagnosed with HIV type 1 infection since 1998, underhighly active antiretroviral treatment （HAART）, withvirological suppression and immunological recovery.He presented in a follow-up laboratory workup highvalues of transaminases, arthralgia at the hip joints and hepatomegaly. Liver function tests were normal. Theantibodies to hepatitis viruses were negative. However,autoimmune study and liver biopsy were compatible with autoimmune hepatitis （AIH）. The AIH is a rare di-agnosis in HIV-infected patients perhaps because the elevation of transaminases and changes in liver function tests are often associated to HAART or to other possible liver diseases, namely viral hepatitis and non-alcoholic steatohepatitis. The diagnosis may be underestimated. There are no specifc recommendations available for the treatment of HIV-associated AIH although the immuno-supression with slower tapering seems the most reason-able approach.展开更多
The development of a vaccine based on human immunodeficiency virus type 1(HIV-1) envelope glycoprotein(Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the a...The development of a vaccine based on human immunodeficiency virus type 1(HIV-1) envelope glycoprotein(Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the antibody production patterns of HIV-1 Env gp120 and hepatitis B virus surface antigen(HBsAg) to provide insights into how we may improve the protective efficacy of Env-based immunogens. Our previous study showed that HIV Env and HBsAg display different mechanisms of antibody elicitation and that T cells facilitate the responses to repeated immunizations. Here, to elucidate the detailed roles of primary immunization in immune memory response formation and antibody production, we immunized C57BL/6 mice with each antigen and evaluated the development of T follicular helper(Tfh) cells, germinal centers,and the memory responses involved in prime and boost immunizations. We found that after prime immunization, compared with HBsAg, gp120 induced higher frequencies of Tfh cells and programmed death(PD)-1^+T cells, greater major histocompatibility complex II expression on B cells, comparable activated B cells, but weaker germinal center(GC)reactions and memory B cell responses in the draining lymph nodes, accompanied by slower antibody recall responses and poor immune memory responses. The above results suggested that more PD-1^+T cells arising in primary immunization may serve as major contributors to the slow antibody recall response elicited by HIV-1 Env.展开更多
Various kinds of organisms, including viruses, bacteria, trematodes and fungi are known carcinogens that cause cancer. Infectious identification related to cancer may lead to better treatment for both the prevention a...Various kinds of organisms, including viruses, bacteria, trematodes and fungi are known carcinogens that cause cancer. Infectious identification related to cancer may lead to better treatment for both the prevention and targeting of cancer therapy. Although nearly 20% of all cancers are caused by an infection of a microbe, the amount of evidence and information regarding the mechanisms associated with oncogenesis varies dramatically from one organism to the next. This review cannot be exhaustive because we are not aware of all infections worldwide in addition to their potential mechanisms for oncogenesis. More research is required for all of the species mentioned in this review.展开更多
基金Supported by the National Natural Science Foundation of China,No. 30200232
文摘AIM： To assess the associations of human leukocyte antigen （HI_A） class Ⅱ DQB1＊0301 and/or DRB1＊1101 allele with spontaneous hepatitis C virus （HCV） clearance by meta-analysis of individual dataset from all studies published till date. METHODS： To clarify the impact of HLA class Ⅱ polymorphisms on viral clearance, we performed a metaanalysis of the published data from 11 studies comparing the frequencies of DQB1＊0301 and DRB1＊1101 alleles in individuals with spontaneous resolution to those with persistent infection. As we identified the heterogeneity between studies, summary statistical data were calculated based on a random-effect model. RESULTS： Meta-analyses yielded summary estimatesodds ratio （OR） of 2.36 [95%CI （1.62, 3.43）, P〈0.00001] and 2.02 [95%CI （1.56, 2.62）, P〈0.00001] for the effects of DQB1＊0301 and DRB1＊1101 alleles on spontaneous clearance of HCV, respectively. CONCLUSION： These results support the hypothesis that specific HLA class Ⅱ alleles might influence the susceptibility or resistance to persistent HCV infection. Both DQB1＊0301 and DRB1＊1101 are protective alleles and present HCV epitopes more effectively to CD4^＋T lymphocytes than others, and subjects with these two alleles are at a lower risk of developing chronic HCV infection. Large, multi-ethnic confirmatory and welldesigned studies are needed to determine the host genetic determinants of HCV infection.
基金Supported by Key Program of National Natural Science Foundation of China, No. 30730085Zhejiang Provincial Natural Science Foundation, No. Y2110169Zhejiang Provincial Natural Science Foundation, No. Y207465
文摘AIM: To further investigate the role of human B7 homolog 1 (B7-H1) in the mechanism of persistent hepatitis B virus (HBV) infection. METHODS: Peripheral and intra-hepatic B7-H1 expression were compared by flow cytometry and immunochemical staining between two 2 distinct groups, one being chronic HBV tolerance patients (CHB-T) and the other being acute hepatitis B patients (AHB). B7-H1 mRNA expression level was also compared by real time polymerase chain reaction between CHB-T and AHB patients. The location of intra-hepatic B7-H1 and CD40 expression were analyzed by immunofluorescence. The levels of B7-H1 and CD40 expression on cultured myeloid dendritic cells (mDCs) with or without hepatitis B surface antigen (HBsAg) treatment were analyzed dynamically by flow cytometry. Intracellular interferon-γ (IFN-γ) staining and the stimulatory capacity of mDC of cultured mDC with or without HBsAg treatment were also compared by flow cytometry. RESULTS: Peripheral B7-H1 expression on mDCs was increased significantly in AHB compared to CHB-T patients (P < 0.05). In the liver tissues from CHB-T patients, B7-H1 positive cells were almost absent despite a persistently elevated serum HBsAg load. In contrast, there were indeed increased B7-H1-positive cells in situ in the liver tissue from AHB. In vitro analysis showed the parallel upregulation of B7-H1 and CD40 on CD11c+ mDCs after the onset of stimulation. Addition of recombinant hepatitis B surface antigen (rHBsAg) significantly decreased CD40 expression (P < 0.05 at 16 h, 20 h and 24 h time points). B7-H1 expression was also inhibited by rHBsAg, and the inhibition rate of CD40 was greater than that of B7-H1. This preferential inhibition of CD40 expression on mDCs by rHBsAg resulted in the dysfunction of mDCs and T cells in the mixed leucocyte reaction (MLR) system. With rHBsAg pretreatment, in a carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled MLR system at a ratio of 1:5 responder cell-stimulator cell (R/S), the CFSE dim percentage of T cells decreased from 85.1% to 25.4% and decreased from 30.3% to 12.0% at 1:10 R/S. IFN-γ production by CD8+ T cells, in the MLR system, was reduced significantly by HBsAg pretreatment. At ratios of 1:5 R/S, the percentage of IFN-γ and CD8 dual positive T cells decreased from 55.2% ± 5.3% to 15.1% ±3.1% (P < 0.001), and decreased from 35.0% ± 5.1% to 7.3% ± 2.7% at ratios of 1:10 R/S (P < 0.001). CONCLUSION: B7-H1 is not a signature of immune dysfunction, but an inflammation marker. HBsAg regulate immune response by tipping the balance between B7-H1 and CD40.
文摘This review analyses current data concerning co-infection with hepatitis C virus(HCV) and human T lymphotropic virus(HTLV)-1/2 in people who inject drugs(PWID), with a particular focus on disease burden and global implications for virological outcome. In addition, the available treatment options for HTLV-1/2 are summarized and the on-going and likely future research challenges are discussed. The data in this review was obtained from 34 articles on HCV/HTLV-1/2 co-infection in PWID retrieved from the Pub Med literature database and published between 1997 and 2015. Despite unavailable estimates of the burden of HCV/HTLV-1/2 co-infection in general, the epidemiologic constellation of HTLV-1/2 shows high incidence in PWID with history of migration, incarceration, and other blood-borne infectious diseases such as HCV or human immunodeficiency virus. The most recent research data strongly suggest that HTLV-1 co-infection can influence HCV viral load, HCV sustained virological response to α-interferon treatment, and HCV-related liver disease progression. In short, outcome of HCV infection is worse in the context of HTLV-1 co-infection, yet more studies are needed to gain accurate estimations of the burden of HCV/HTLV-1/2 co-infections. Moreover, in the current era of new direct-acting antiviral treatments for HCV and proven HTLV-1/2 treatment options, prospective clinical and treatment studies should be carried out, with particular focus on the PWID patient population, with the aim of improving virological outcomes.
基金the Deutsche Forschungsgemeinschaft (Emmy Noether Programm, SFB 610)the Wilhelm Sander Stiftung, and the Bundesministerium fuer Wissenschaft und Forschung (Start-up fonds Kompetenznetz Hepatitis)
文摘Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.
文摘Liver disease has recently been described as an im-portant cause of morbidity and mortality in patientsinfected with human immunodeficiency virus （HIV）.Liver test changes are useful surrogates of the burdenof liver disease. Previous studies have shown that trans-aminase elevations are frequent among these patients.The cause of those changes is harder to establish inHIV-patients. We present a 61-year-old caucasian male,diagnosed with HIV type 1 infection since 1998, underhighly active antiretroviral treatment （HAART）, withvirological suppression and immunological recovery.He presented in a follow-up laboratory workup highvalues of transaminases, arthralgia at the hip joints and hepatomegaly. Liver function tests were normal. Theantibodies to hepatitis viruses were negative. However,autoimmune study and liver biopsy were compatible with autoimmune hepatitis （AIH）. The AIH is a rare di-agnosis in HIV-infected patients perhaps because the elevation of transaminases and changes in liver function tests are often associated to HAART or to other possible liver diseases, namely viral hepatitis and non-alcoholic steatohepatitis. The diagnosis may be underestimated. There are no specifc recommendations available for the treatment of HIV-associated AIH although the immuno-supression with slower tapering seems the most reason-able approach.
基金supported by the Grant of National Natural Science Foundation of China (Grant number 81271824, 81772190, 81601755)the Grant of National Science and Technology Major Project (Grant number 2012ZX10001009-002003)
文摘The development of a vaccine based on human immunodeficiency virus type 1(HIV-1) envelope glycoprotein(Env) that elicits potent protective antibodies against infection has been challenging. Recently, we compared the antibody production patterns of HIV-1 Env gp120 and hepatitis B virus surface antigen(HBsAg) to provide insights into how we may improve the protective efficacy of Env-based immunogens. Our previous study showed that HIV Env and HBsAg display different mechanisms of antibody elicitation and that T cells facilitate the responses to repeated immunizations. Here, to elucidate the detailed roles of primary immunization in immune memory response formation and antibody production, we immunized C57BL/6 mice with each antigen and evaluated the development of T follicular helper(Tfh) cells, germinal centers,and the memory responses involved in prime and boost immunizations. We found that after prime immunization, compared with HBsAg, gp120 induced higher frequencies of Tfh cells and programmed death(PD)-1^+T cells, greater major histocompatibility complex II expression on B cells, comparable activated B cells, but weaker germinal center(GC)reactions and memory B cell responses in the draining lymph nodes, accompanied by slower antibody recall responses and poor immune memory responses. The above results suggested that more PD-1^+T cells arising in primary immunization may serve as major contributors to the slow antibody recall response elicited by HIV-1 Env.
文摘Various kinds of organisms, including viruses, bacteria, trematodes and fungi are known carcinogens that cause cancer. Infectious identification related to cancer may lead to better treatment for both the prevention and targeting of cancer therapy. Although nearly 20% of all cancers are caused by an infection of a microbe, the amount of evidence and information regarding the mechanisms associated with oncogenesis varies dramatically from one organism to the next. This review cannot be exhaustive because we are not aware of all infections worldwide in addition to their potential mechanisms for oncogenesis. More research is required for all of the species mentioned in this review.
