Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is pre...Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) response.These chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors.Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C.The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection.When the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic damage.The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell migration.Some chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome.The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.展开更多
Ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. Viral entry/infection is initiated by binding of glycoprotein GP protein on Ebola virion to host cells, follow...Ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. Viral entry/infection is initiated by binding of glycoprotein GP protein on Ebola virion to host cells, followed by fusion of virus-cell membrane also mediated by GP. Using an human immunodeficiency virus (HIV)-based pseudotyping system, the roles of 41 Ebola GP1 residues in the receptor-binding domain in viral entry were studied by alanine scanning substitutions. We identified that four residues appear to be involved in protein folding/structure and four residues are important for viral entry. An improved entry interference assay was developed and used to study the role of these residues that are important for viral entry. It was found that R64 and K95 are involved in receptor binding. In contrast, some residues such as I170 are important for viral entry, but do not play a major role in receptor binding as indicated by entry interference assay and/or protein binding data, suggesting that these residues are involved in post-binding steps of viral entry. Furthermore, our results also suggested that Ebola and Marburg viruses share a common cellular molecule for entry.展开更多
Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV) share common risk factors and HBV occurs in people with HIV resulting in an increased risk for HIV/HBV co-infection. Globally, hepatitis B virus infection...Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV) share common risk factors and HBV occurs in people with HIV resulting in an increased risk for HIV/HBV co-infection. Globally, hepatitis B virus infection is of serious public health causing morbidity and mortality. The increasing incidence of liver diseases caused by HBV is emerging as a significant cause of morbidity and mortality among HIV-infected individuals. A clearer knowledge of HBV prevalence in Kogi State is important in order to educate, inform the population and control epidemics through extensive vaccination and treatment programme. The aim of this study was to determine the seroprevalence of Hepatitis B infection and to evaluate molecularly HBV infection among HIV seropositive individuals. Sera samples were obtained from 218 consented HIV participants and screened for HBsAg using the commercial membrane based rapid qualitative test kit and real-time PCR was performed using Tianlong to assay the virus quantitatively. A structured questionnaire was used to collect information on patient’s demographic variables and risk factors for HBV transmission. Overall, 17 of the participants were seropositive to HBsAg. There was a significant difference between the age distribution with (P-value = 0.006) and marital status with (P-value = 0.044). Type of marriage, occupation, place of residence and risk factors associated with HIV and HBV co-infection do not show significant differences. A total of 17 HBsAg positive samples were subjected to viral load analysis, out of which 7 were highly unsuppressed, 5 were suppressed while the remaining 5 were undetectable. This study confirmed a moderately high HIV/HBV co-infection rate (7.8%). The highly unsuppressed viral load obtained from the study is a potential risk for Hepatocellular carcinoma among the study population. Enlightenment programme on routes of virus acquisition with a view to reducing the morbidity and mortality of HIV/HBV co-infection should be intensified.展开更多
The human CD81(hCD81),the most recently proposed receptor of hepatitis C virus(HCV),can especifically bind to HCV envelope glycoprotein 2(E2).In this study,hCD81-expressing murine NIH/3T3 cells were used to select hCD...The human CD81(hCD81),the most recently proposed receptor of hepatitis C virus(HCV),can especifically bind to HCV envelope glycoprotein 2(E2).In this study,hCD81-expressing murine NIH/3T3 cells were used to select hCD81-binding peptides from a phage displayed nonapeptide library(PVIII9aaCys).Eighteen of the 75clones selected from the library showed specific binding to the hCD81-expressing NIH/3T3 cells by enzyme linked immunosorbent assay(ELISA)and competitive inhibition test.Twelve out of the 18 clones shared the amino acid motif SPQYWTGPA.Sequence comparison of the motif showed no amino acid homology with the native HCV E2.The motif-containing phages could competitively inhibit the ability of HCV E2 binding to native hCD81-expressing MOLT-4 cells,and induce HCV E2 specific immune response in vivo.These results suggest that the selected motif SPQYWTGPA should be a mimotope of HCV E2 to bind to hCD81 molecules.Our findings cast new light on developing HCV receptor antagonists.展开更多
Hepadnaviridae is a family of hepatotropic DNA viruses that is divided into the genera orthohepadnavirus of mammals and avihepadnavirus of birds.All members of this family can cause acute and chronic hepatic infec-tio...Hepadnaviridae is a family of hepatotropic DNA viruses that is divided into the genera orthohepadnavirus of mammals and avihepadnavirus of birds.All members of this family can cause acute and chronic hepatic infec-tion,which in the case of human hepatitis B virus(HBV) constitutes a major global health problem.Although our knowledge about the molecular biology of these highly liver-specific viruses has profoundly increased in the last two decades,the mechanisms of attachment and productive entrance into the differentiated host hepa-tocytes are still enigmatic.The difficulties in studying hepadnaviral entry were primarily caused by the lack of easily accessible in vitro infection systems.Thus,for more than twenty years,differentiated primary hepato-cytes from the respective species were the only in vitro models for both orthohepadnaviruses(e.g.HBV) and avihepadnaviruses(e.g.duck hepatitis B virus [DHBV]).Two important discoveries have been made recently re-garding HBV:(1) primary hepatocytes from tree-shrews;i.e.,Tupaia belangeri,can be substituted for primary hu-man hepatocytes,and(2) a human hepatoma cell line(HepaRG) was established that gains susceptibility for HBV infection upon induction of differentiation in vitro.A number of potential HBV receptor candidates have been described in the past,but none of them have been confirmed to function as a receptor.For DHBV and prob-ably all other avian hepadnaviruses,carboxypeptidase D(CPD) has been shown to be indispensable for infection,although the exact role of this molecule is still under debate.While still restricted to the use of primary duck hepatocytes(PDH),investigations performed with DHBV provided important general concepts on the first steps of hepadnaviral infection.However,with emerging dataobtained from the new HBV infection systems,the hope that DHBV utilizes the same mechanism as HBV only partially held true.Nevertheless,both HBV and DHBV in vitro infection systems will help to:(1) functionally dis-sect the hepadnaviral entry pathways,(2) perform re-verse genetics(e.g.test the fitness of escape mutants),(3) titrate and map neutralizing antibodies,(4) improve current vaccines to combat acute and chronic infections of hepatitis B,and(5) develop entry inhibitors for future clinical applications.展开更多
Heparan sulfate （HS） is ubiquitously expressed on the surfaces and in the extracellular matrix of virtually all cell types, making it an ideal receptor for viral infection. Compared with wild‐type viruses, cell cul...Heparan sulfate （HS） is ubiquitously expressed on the surfaces and in the extracellular matrix of virtually all cell types, making it an ideal receptor for viral infection. Compared with wild‐type viruses, cell culture‐adapted laboratory strains exhibit more efficient binding to cellular HS receptors. HS‐binding viruses are typically cleared faster from the circulation and cause lower viremia than their non‐HS‐binding counterparts, suggesting that the HS‐binding phenotype is a tissue culture adaptation that lowers virus fitness in vivo. However, when inoculated intracranially, efficient cell attachment through HS binding can contribute to viral neurovirulence. The primary aim of this review is to discuss the roles of HS binding in viral pathogenicity, including peripheral virulence and neurovirulence. Understanding how heparan sulfate functions during virus infection in vivo may prove critical for elucidating the molecular mechanism of viral pathogenesis, and may contribute to the development of therapeutics targeting HS.展开更多
Integrins are members of a ubiquitous membrane receptor family which includes 18 different α subunits and 8 β subunits forming more than 20 α/β heterodimers. Integrins play key functions in vascular endothelial ce...Integrins are members of a ubiquitous membrane receptor family which includes 18 different α subunits and 8 β subunits forming more than 20 α/β heterodimers. Integrins play key functions in vascular endothelial cell and tumour cell adhesion, lymphocyte trafficking, tumor growth and viral infection. Current understanding of the molecular basis of integrins as viral receptors has been achieved through many decades of study into the biology of transmembrane glycoproteins and their interactions with several viruses. This review provides a summary of the current knowledge on the molecular bases of interactions between viruses and integrins, which are of potential practical significance. Inhibition of virus-integrin interactions at the points of virus attachment or entry will provide a novel approach for the therapeutic treatment of viral diseases.展开更多
基金Supported by Grants from "Fiscam" J.C.C.M (Ayuda paraproyectos de investigación en saludPI-2007/32)+7 种基金"AsociaciónCastellana de Aparato Digestivo" (Beca ACADACAD/06)"Fundación de Investigación Médica Mutua Madrilea"(Beca Ayudas a la Investigación FMMM2548/2008),Spainsupported by a research grantfrom "Fiscam" J.C.C.M ("Perfeccionamiento y movilidad deinvestigadores" MOV-2007_JI/18), Spainsupported by a research grant from "Instituto de SaludCarlos Ⅲ" (Contrato de apoyo a la investigación en el SNS"CA07/00157),Spain
文摘Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) response.These chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors.Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C.The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection.When the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic damage.The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell migration.Some chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome.The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.
基金National Institutes of Health Grant (AI059570 and AI077767)
文摘Ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. Viral entry/infection is initiated by binding of glycoprotein GP protein on Ebola virion to host cells, followed by fusion of virus-cell membrane also mediated by GP. Using an human immunodeficiency virus (HIV)-based pseudotyping system, the roles of 41 Ebola GP1 residues in the receptor-binding domain in viral entry were studied by alanine scanning substitutions. We identified that four residues appear to be involved in protein folding/structure and four residues are important for viral entry. An improved entry interference assay was developed and used to study the role of these residues that are important for viral entry. It was found that R64 and K95 are involved in receptor binding. In contrast, some residues such as I170 are important for viral entry, but do not play a major role in receptor binding as indicated by entry interference assay and/or protein binding data, suggesting that these residues are involved in post-binding steps of viral entry. Furthermore, our results also suggested that Ebola and Marburg viruses share a common cellular molecule for entry.
文摘Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV) share common risk factors and HBV occurs in people with HIV resulting in an increased risk for HIV/HBV co-infection. Globally, hepatitis B virus infection is of serious public health causing morbidity and mortality. The increasing incidence of liver diseases caused by HBV is emerging as a significant cause of morbidity and mortality among HIV-infected individuals. A clearer knowledge of HBV prevalence in Kogi State is important in order to educate, inform the population and control epidemics through extensive vaccination and treatment programme. The aim of this study was to determine the seroprevalence of Hepatitis B infection and to evaluate molecularly HBV infection among HIV seropositive individuals. Sera samples were obtained from 218 consented HIV participants and screened for HBsAg using the commercial membrane based rapid qualitative test kit and real-time PCR was performed using Tianlong to assay the virus quantitatively. A structured questionnaire was used to collect information on patient’s demographic variables and risk factors for HBV transmission. Overall, 17 of the participants were seropositive to HBsAg. There was a significant difference between the age distribution with (P-value = 0.006) and marital status with (P-value = 0.044). Type of marriage, occupation, place of residence and risk factors associated with HIV and HBV co-infection do not show significant differences. A total of 17 HBsAg positive samples were subjected to viral load analysis, out of which 7 were highly unsuppressed, 5 were suppressed while the remaining 5 were undetectable. This study confirmed a moderately high HIV/HBV co-infection rate (7.8%). The highly unsuppressed viral load obtained from the study is a potential risk for Hepatocellular carcinoma among the study population. Enlightenment programme on routes of virus acquisition with a view to reducing the morbidity and mortality of HIV/HBV co-infection should be intensified.
基金supported by research grants from the National Natural Science Foundation of China(No.30271l87)the Shanghai Science and Technology Development Foundation(No.02DJ14015)
文摘The human CD81(hCD81),the most recently proposed receptor of hepatitis C virus(HCV),can especifically bind to HCV envelope glycoprotein 2(E2).In this study,hCD81-expressing murine NIH/3T3 cells were used to select hCD81-binding peptides from a phage displayed nonapeptide library(PVIII9aaCys).Eighteen of the 75clones selected from the library showed specific binding to the hCD81-expressing NIH/3T3 cells by enzyme linked immunosorbent assay(ELISA)and competitive inhibition test.Twelve out of the 18 clones shared the amino acid motif SPQYWTGPA.Sequence comparison of the motif showed no amino acid homology with the native HCV E2.The motif-containing phages could competitively inhibit the ability of HCV E2 binding to native hCD81-expressing MOLT-4 cells,and induce HCV E2 specific immune response in vivo.These results suggest that the selected motif SPQYWTGPA should be a mimotope of HCV E2 to bind to hCD81 molecules.Our findings cast new light on developing HCV receptor antagonists.
基金Supported by grant SFB535/A2 from DFG, EU QLK 2000- 01476 and DFG UR72/1-3, UR72/1-4
文摘Hepadnaviridae is a family of hepatotropic DNA viruses that is divided into the genera orthohepadnavirus of mammals and avihepadnavirus of birds.All members of this family can cause acute and chronic hepatic infec-tion,which in the case of human hepatitis B virus(HBV) constitutes a major global health problem.Although our knowledge about the molecular biology of these highly liver-specific viruses has profoundly increased in the last two decades,the mechanisms of attachment and productive entrance into the differentiated host hepa-tocytes are still enigmatic.The difficulties in studying hepadnaviral entry were primarily caused by the lack of easily accessible in vitro infection systems.Thus,for more than twenty years,differentiated primary hepato-cytes from the respective species were the only in vitro models for both orthohepadnaviruses(e.g.HBV) and avihepadnaviruses(e.g.duck hepatitis B virus [DHBV]).Two important discoveries have been made recently re-garding HBV:(1) primary hepatocytes from tree-shrews;i.e.,Tupaia belangeri,can be substituted for primary hu-man hepatocytes,and(2) a human hepatoma cell line(HepaRG) was established that gains susceptibility for HBV infection upon induction of differentiation in vitro.A number of potential HBV receptor candidates have been described in the past,but none of them have been confirmed to function as a receptor.For DHBV and prob-ably all other avian hepadnaviruses,carboxypeptidase D(CPD) has been shown to be indispensable for infection,although the exact role of this molecule is still under debate.While still restricted to the use of primary duck hepatocytes(PDH),investigations performed with DHBV provided important general concepts on the first steps of hepadnaviral infection.However,with emerging dataobtained from the new HBV infection systems,the hope that DHBV utilizes the same mechanism as HBV only partially held true.Nevertheless,both HBV and DHBV in vitro infection systems will help to:(1) functionally dis-sect the hepadnaviral entry pathways,(2) perform re-verse genetics(e.g.test the fitness of escape mutants),(3) titrate and map neutralizing antibodies,(4) improve current vaccines to combat acute and chronic infections of hepatitis B,and(5) develop entry inhibitors for future clinical applications.
基金supported by grants from the National Natural Science Foundation of China (No. 30970160)the Major Science and Technology Project for Infectious Disease (No. 2008ZX10004‐001+1 种基金 2009ZX10004‐705)the Development Grant of the State Key Laboratory for Infectious Disease Prevention and Control (2008SKLID105)
文摘Heparan sulfate （HS） is ubiquitously expressed on the surfaces and in the extracellular matrix of virtually all cell types, making it an ideal receptor for viral infection. Compared with wild‐type viruses, cell culture‐adapted laboratory strains exhibit more efficient binding to cellular HS receptors. HS‐binding viruses are typically cleared faster from the circulation and cause lower viremia than their non‐HS‐binding counterparts, suggesting that the HS‐binding phenotype is a tissue culture adaptation that lowers virus fitness in vivo. However, when inoculated intracranially, efficient cell attachment through HS binding can contribute to viral neurovirulence. The primary aim of this review is to discuss the roles of HS binding in viral pathogenicity, including peripheral virulence and neurovirulence. Understanding how heparan sulfate functions during virus infection in vivo may prove critical for elucidating the molecular mechanism of viral pathogenesis, and may contribute to the development of therapeutics targeting HS.
基金The National key Basic Research (973)Program (2005CB523201)National Key TechnologyR&D Program (2006BAD06A14)
文摘Integrins are members of a ubiquitous membrane receptor family which includes 18 different α subunits and 8 β subunits forming more than 20 α/β heterodimers. Integrins play key functions in vascular endothelial cell and tumour cell adhesion, lymphocyte trafficking, tumor growth and viral infection. Current understanding of the molecular basis of integrins as viral receptors has been achieved through many decades of study into the biology of transmembrane glycoproteins and their interactions with several viruses. This review provides a summary of the current knowledge on the molecular bases of interactions between viruses and integrins, which are of potential practical significance. Inhibition of virus-integrin interactions at the points of virus attachment or entry will provide a novel approach for the therapeutic treatment of viral diseases.
