The Experts below are selected from a list of 18081 Experts worldwide ranked by ideXlab platform
Harvey M Friedman - One of the best experts on this subject based on the ideXlab platform.
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immunization with hsv 1 glycoprotein c prevents immune evasion from Complement and enhances the efficacy of an hsv 1 glycoprotein d subunit vaccine
Vaccine, 2009Co-Authors: Sita Awasthi, John M Lubinski, Harvey M FriedmanAbstract:Herpes simplex virus type 1 (HSV-1) glycoprotein C (gC-1) binds Complement Component C3b and inhibits Complement-mediated immunity. HSV-1 glycoprotein D (gD-1) is a potent immunogen and a candidate antigen for a subunit vaccine. We evaluated whether combined immunization with gD-1 and gC-1 provides better protection against challenge than gD-1 alone based on antibodies to gC-1 preventing HSV-1-mediated immune evasion. IgG purified from mice immunized with gC-1 blocked C3b binding to gC-1 and greatly increased neutralization by gD-1 IgG in the presence of Complement. Passive transfer of gC-1 IgG protected Complement intact mice against HSV-1 challenge but not C3 knockout mice, indicating that gC-1 antibody activity in vivo is Complement-dependent. Immunizing mice with gD-1 and gC-1 provided better protection than gD-1 alone in preventing zosteriform disease and infection of dorsal root ganglia. Therefore, gC-1 immunization prevents HSV-1 evasion from Complement and enhances the protection provided by gD-1 immunization.
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herpes simplex virus type 1 and 2 glycoprotein c prevents Complement mediated neutralization induced by natural immunoglobulin m antibody
Journal of Virology, 2006Co-Authors: Lauren M Hook, John M Lubinski, Ming Jiang, Michael K Pangburn, Harvey M FriedmanAbstract:Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) binds Complement Component C3b and protects virus from Complement-mediated neutralization. Differences in Complement interacting domains exist between gC of HSV-1 (gC1) and HSV-2 (gC2), since the amino terminus of gC1 blocks Complement C5 from binding to C3b, while gC2 fails to interfere with this activity. We previously reported that neutralization of HSV-1 gC-null virus by HSV antibody-negative human serum requires activation of C5 but not of downstream Components of the classical Complement pathway. In this report, we evaluated whether activation of C5 is sufficient to neutralize HSV-2 gC-null virus, or whether formation of the membrane attack complex by C6 to C9 is required for neutralization. We found that activation of the classical Complement pathway up to C5 was sufficient to neutralize HSV-2 gC-null virus by HSV antibody-negative human serum. We evaluated the mechanisms by which Complement activation occurred in seronegative human serum. Interestingly, natural immunoglobulin M antibodies bound to virus, which triggered activation of C1q and the classical Complement pathway. HSV antibody-negative sera obtained from four individuals differed over an approximately 10-fold range in their potency for Complement-mediated virus neutralization. These findings indicate that humans differ in the ability of their innate immune systems to neutralize HSV-1 or HSV-2 gC-null virus and that a critical function of gC1 and gC2 is to prevent C5 activation.
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kinetic analysis of glycoprotein c of herpes simplex virus types 1 and 2 binding to heparin heparan sulfate and Complement Component C3b
Virology, 2002Co-Authors: Ann H Rux, John D. Lambris, Huan Lou, Harvey M Friedman, Roselyn J Eisenberg, Gary H CohenAbstract:Abstract Glycoprotein C (gC) from herpes simplex virus (HSV) facilitates virus entry by attaching the virion to host cell-surface heparan sulfate (HS). Although gC from HSV-1 (gC1) and from HSV-2 (gC2) bind to heparin, gC2 is believed to play a less significant role than gC1 in attachment of virus to cells. This attachment step is followed by the binding of gD to one of several cellular receptors. gC also plays an important role in immune evasion by binding to the C3b fragment of the third Component of the host Complement system. Yet, although both gC1 and gC2 protect HSV against Complement-mediated neutralization, only gC on HSV-1-infected cells acts as a receptor for C3b. We used optical biosensor technology to quantitate the affinities ( K D ) and the stabilities ( k off ) between both serotypes of gC with heparin, HS, and C3b to address three questions concerning gC interactions. First, can differences in affinity or stability account for differences between the contributions of HSV-1 and HSV-2 gC in attachment? Our data show that the gC2–HS complex is highly unstable ( k off = 0.2 s −1 ) compared to the gC1–HS complex ( k off = 0.003 s −1 ), suggesting why gC2 may not play an important role in attachment of virus to cells as does gC1. Second, does gC2 have a lower affinity for C3b than does gC1, thereby explaining the lack of C3b-receptor activity on HSV-2 infected cells? Surprisingly, gC2 had a 10-fold higher affinity for C3b compared to gC1, so this functional difference in serotypes cannot be accounted for by affinity. Third, do differences in gC–HS and gD-receptor affinities support a model of HSV entry in which the gC–HS interaction is of lower affinity than the gD-receptor interaction? Our biosensor results indicate that gC has a higher affinity for HS than gD does for cellular receptors HveA (HVEM) and HveC (nectin-1).
John M Lubinski - One of the best experts on this subject based on the ideXlab platform.
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immunization with hsv 1 glycoprotein c prevents immune evasion from Complement and enhances the efficacy of an hsv 1 glycoprotein d subunit vaccine
Vaccine, 2009Co-Authors: Sita Awasthi, John M Lubinski, Harvey M FriedmanAbstract:Herpes simplex virus type 1 (HSV-1) glycoprotein C (gC-1) binds Complement Component C3b and inhibits Complement-mediated immunity. HSV-1 glycoprotein D (gD-1) is a potent immunogen and a candidate antigen for a subunit vaccine. We evaluated whether combined immunization with gD-1 and gC-1 provides better protection against challenge than gD-1 alone based on antibodies to gC-1 preventing HSV-1-mediated immune evasion. IgG purified from mice immunized with gC-1 blocked C3b binding to gC-1 and greatly increased neutralization by gD-1 IgG in the presence of Complement. Passive transfer of gC-1 IgG protected Complement intact mice against HSV-1 challenge but not C3 knockout mice, indicating that gC-1 antibody activity in vivo is Complement-dependent. Immunizing mice with gD-1 and gC-1 provided better protection than gD-1 alone in preventing zosteriform disease and infection of dorsal root ganglia. Therefore, gC-1 immunization prevents HSV-1 evasion from Complement and enhances the protection provided by gD-1 immunization.
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herpes simplex virus type 1 and 2 glycoprotein c prevents Complement mediated neutralization induced by natural immunoglobulin m antibody
Journal of Virology, 2006Co-Authors: Lauren M Hook, John M Lubinski, Ming Jiang, Michael K Pangburn, Harvey M FriedmanAbstract:Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) binds Complement Component C3b and protects virus from Complement-mediated neutralization. Differences in Complement interacting domains exist between gC of HSV-1 (gC1) and HSV-2 (gC2), since the amino terminus of gC1 blocks Complement C5 from binding to C3b, while gC2 fails to interfere with this activity. We previously reported that neutralization of HSV-1 gC-null virus by HSV antibody-negative human serum requires activation of C5 but not of downstream Components of the classical Complement pathway. In this report, we evaluated whether activation of C5 is sufficient to neutralize HSV-2 gC-null virus, or whether formation of the membrane attack complex by C6 to C9 is required for neutralization. We found that activation of the classical Complement pathway up to C5 was sufficient to neutralize HSV-2 gC-null virus by HSV antibody-negative human serum. We evaluated the mechanisms by which Complement activation occurred in seronegative human serum. Interestingly, natural immunoglobulin M antibodies bound to virus, which triggered activation of C1q and the classical Complement pathway. HSV antibody-negative sera obtained from four individuals differed over an approximately 10-fold range in their potency for Complement-mediated virus neutralization. These findings indicate that humans differ in the ability of their innate immune systems to neutralize HSV-1 or HSV-2 gC-null virus and that a critical function of gC1 and gC2 is to prevent C5 activation.
Richard M Jack - One of the best experts on this subject based on the ideXlab platform.
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the role of Complement Component C3b and its receptors in sperm oocyte interaction
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Deborah J Anderson, Amy F Abbott, Richard M JackAbstract:Previous studies have shown that human sperm that have undergone the acrosome reaction express a unique tissue-specific variant of the Complement Component 3 (C3)-binding molecule membrane cofactor protein (MCP, CD46) and that damaged or dead sperm activate the alternative pathway of Complement and bind C3 catabolites. In this study we provide evidence that MCP on sperm that have undergone the acrosome reaction specifically binds dimeric C3b and that human sperm acrosomal proteases released during the acrosome reaction directly cleave C3, facilitating its binding to MCP. Furthermore, human and hamster oocytes can activate the alternative pathway of Complement and also bind human C3 fragments. Monoclonal antibodies specific for Complement receptors type 1 (CD35) and type 3 (CD11b/CD18) bind to the human oocyte plasma membrane, indicating that specific Complement-binding molecules may play a role in the attachment of C3 catabolites to oocytes. Subsaturating concentrations of dimeric C3b (0.01-1 microM) promoted penetration of hamster oocytes by human sperm, whereas saturating doses (> 10 microM) inhibited this process. In addition, antibodies to both MCP and C3 significantly inhibited penetration of hamster oocytes by human sperm. These data provide evidence that regulated gamete-induced generation of C3 fragments and the binding of these fragments by selectively expressed receptors on sperm and oocytes may be an initial step in gamete interaction, leading to membrane fusion and fertilization.
Gary H Cohen - One of the best experts on this subject based on the ideXlab platform.
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kinetic analysis of glycoprotein c of herpes simplex virus types 1 and 2 binding to heparin heparan sulfate and Complement Component C3b
Virology, 2002Co-Authors: Ann H Rux, John D. Lambris, Huan Lou, Harvey M Friedman, Roselyn J Eisenberg, Gary H CohenAbstract:Abstract Glycoprotein C (gC) from herpes simplex virus (HSV) facilitates virus entry by attaching the virion to host cell-surface heparan sulfate (HS). Although gC from HSV-1 (gC1) and from HSV-2 (gC2) bind to heparin, gC2 is believed to play a less significant role than gC1 in attachment of virus to cells. This attachment step is followed by the binding of gD to one of several cellular receptors. gC also plays an important role in immune evasion by binding to the C3b fragment of the third Component of the host Complement system. Yet, although both gC1 and gC2 protect HSV against Complement-mediated neutralization, only gC on HSV-1-infected cells acts as a receptor for C3b. We used optical biosensor technology to quantitate the affinities ( K D ) and the stabilities ( k off ) between both serotypes of gC with heparin, HS, and C3b to address three questions concerning gC interactions. First, can differences in affinity or stability account for differences between the contributions of HSV-1 and HSV-2 gC in attachment? Our data show that the gC2–HS complex is highly unstable ( k off = 0.2 s −1 ) compared to the gC1–HS complex ( k off = 0.003 s −1 ), suggesting why gC2 may not play an important role in attachment of virus to cells as does gC1. Second, does gC2 have a lower affinity for C3b than does gC1, thereby explaining the lack of C3b-receptor activity on HSV-2 infected cells? Surprisingly, gC2 had a 10-fold higher affinity for C3b compared to gC1, so this functional difference in serotypes cannot be accounted for by affinity. Third, do differences in gC–HS and gD-receptor affinities support a model of HSV entry in which the gC–HS interaction is of lower affinity than the gD-receptor interaction? Our biosensor results indicate that gC has a higher affinity for HS than gD does for cellular receptors HveA (HVEM) and HveC (nectin-1).
Piet Gros - One of the best experts on this subject based on the ideXlab platform.
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insights into Complement convertase formation based on the structure of the factor b cobra venom factor complex
The EMBO Journal, 2009Co-Authors: Bert J C Janssen, Carlwilhelm Vogel, David C. Fritzinger, Lucio Gomes, Roman I Koning, Dmitri I Svergun, Abraham J Koster, Piet GrosAbstract:Immune protection by the Complement system critically depends on assembly of C3 convertases on the surface of pathogens and altered host cells. These short-lived protease complexes are formed through pro-convertases, which for the alternative pathway consist of the Complement Component C3b and the pro-enzyme factor B (FB). Here, we present the crystal structure at 2.2-A resolution, small-angle X-ray scattering and electron microscopy (EM) data of the pro-convertase formed by human FB and cobra venom factor (CVF), a potent homologue of C3b that generates more stable convertases. FB is loaded onto CVF through its pro-peptide Ba segment by specific contacts, which explain the specificity for the homologous C3b over the native C3 and inactive products iC3b and C3c. The protease segment Bb binds the carboxy terminus of CVF through the metal-ion dependent adhesion site of the Von Willebrand factor A-type domain. A possible dynamic equilibrium between a ‘loading' and ‘activation' state of the pro-convertase may explain the observed difference between the crystal structure of CVFB and the EM structure of C3bB. These insights into formation of convertases provide a basis for further development of Complement therapeutics.