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Anti-Human Immunodeficiency Virus

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Hermann Katinger – One of the best experts on this subject based on the ideXlab platform.

  • comprehensive cross clade neutralization analysis of a panel of anti human Immunodeficiency Virus type 1 monoclonal antibodies
    Journal of Virology, 2004
    Co-Authors: James M Binley, Michael B. Zwick, Meng Wang, Gabriela Stiegler, Renate Kunert, Terri Wrin, Bette T Korber, Colombe Chappey, Susan Zollapazner, Hermann Katinger
    Abstract:

    Broadly neutralizing monoclonal antibodies (MAbs) are potentially important tools in human Immunodeficiency Virus type 1 (HIV-1) vaccine design. A few rare MAbs have been intensively studied, but we still have a limited appreciation of their neutralization breadth. Using a pseudoVirus assay, we evaluated MAbs from clade B-infected donors and a clade B HIV + plasma against 93 Viruses from diverse backgrounds. Anti-gp120 MAbs exhibited greater activity against clade B than non-B Viruses, whereas anti-gp41 MAbs exhibited broad interclade activity. Unexpectedly, MAb 4E10 (directed against the C terminus of the gp41 ectodomain) neutralized all 90 Viruses with moderate potency. MAb 2F5 (directed against an epitope adjacent to that of 4E10) neutralized 67% of isolates, but none from clade C. Anti-gp120 MAb b12 (directed against an epitope overlapping the CD4 binding site) neutralized 50% of Viruses, including some from almost every clade. 2G12 (directed against a high-mannose epitope on gp120) neutralized 41% of the Viruses, but none from clades C or E. MAbs to the gp120 V3 loop, including 447-52D, neutralized a subset of clade B Viruses (up to 45%) but infrequently neutralized other clades (≤7%). MAbs b6 (directed against the CD4 binding site) and X5 (directed against a CD4-induced epitope of gp120) neutralized only sensitive primary clade B Viruses. The HIV + plasma neutralized 70% of the Viruses, including some from all major clades. Further analysis revealed five neutralizing immunotypes that were somewhat associated with clades. As well as the significance for vaccine design, our data have implications for passive-immunization studies in countries where clade C Viruses are common, given that only MAbs b12 and 4E10 were effective against Viruses from this clade.

  • structure and mechanistic analysis of the anti human Immunodeficiency Virus type 1 antibody 2f5 in complex with its gp41 epitope
    Journal of Virology, 2004
    Co-Authors: Gilad Ofek, Hermann Katinger, Min Tang, Anna Sambor, John R Mascola, Richard T Wyatt, Peter D Kwong
    Abstract:

    The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human Immunodeficiency Virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.2-A resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 A in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.

  • characterization of human class switched polymeric immunoglobulin m igm and iga anti human Immunodeficiency Virus type 1 antibodies 2f5 and 2g12
    Journal of Virology, 2003
    Co-Authors: Susanne Wolbank, Gabriela Stiegler, Renate Kunert, Hermann Katinger
    Abstract:

    We have previously generated human monoclonal Anti-Human Immunodeficiency Virus type 1 (anti-HIV-1) antibodies 2F5IgG and 2G12IgG with an exceptional cross-clade neutralizing potential. 2F5IgG and 2G12IgG passively administrated to macaques were able to confer complete protection from both intravenous and mucosal challenge with pathogenic HIV-simian Immunodeficiency Virus chimeric strains and have shown beneficial effects in a phase-1 clinical trial. We now class-switched 2F5 and 2G12 to the immunoglobulin M (IgM) or IgA isotype, to enforce features like avidity, complement activation, or the potential to neutralize mucosal transmission. For this purpose we expressed functional polymeric 2F5 and 2G12 antibodies in CHO cells and evaluated their anti-HIV-1 activity in vitro. The class switch had a strong impact on the protective potential of 2F5 and 2G12. 2G12IgM inhibited HIV-1 infection of peripheral blood mononuclear cell cultures up to 28-fold-more efficiently than the corresponding IgG and neutralized all of the primary isolates tested. The 2F5 and 2G12 antibodies of all isotypes were able to interact with active human serum to inhibit viral infection. Furthermore, we demonstrated that polymeric 2F5 and 2G12 antibodies but not the corresponding IgGs could interfere with HIV-1 entry across a mucosal epithelial layer in vitro. Although polymeric 2F5 antibodies had only limited potential in the standard neutralization assay, the results from the mucosal assay suggest that 2F5 and 2G12 antibodies may have a high potential to prevent natural HIV-1 transmission in vivo.

Charles R. Wira – One of the best experts on this subject based on the ideXlab platform.

  • trappin 2 elafin a novel innate anti human Immunodeficiency Virus 1 molecule of the human female reproductive tract
    Immunology, 2010
    Co-Authors: Mimi Ghosh, Zheng Shen, John V. Fahey, Kenneth H. Mayer, Susan Cuuvin, Charles R. Wira
    Abstract:

    Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an Anti-Human Immunodeficiency Virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when Virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1.

  • Trappin‐2/Elafin: a novel innate anti‐human Immunodeficiency Virus‐1 molecule of the human female reproductive tract
    Immunology, 2010
    Co-Authors: Mimi Ghosh, Zheng Shen, John V. Fahey, Susan Cu-uvin, Kenneth H. Mayer, Charles R. Wira
    Abstract:

    Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an Anti-Human Immunodeficiency Virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when Virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1.

Mimi Ghosh – One of the best experts on this subject based on the ideXlab platform.

  • trappin 2 elafin a novel innate anti human Immunodeficiency Virus 1 molecule of the human female reproductive tract
    Immunology, 2010
    Co-Authors: Mimi Ghosh, Zheng Shen, John V. Fahey, Kenneth H. Mayer, Susan Cuuvin, Charles R. Wira
    Abstract:

    Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an Anti-Human Immunodeficiency Virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when Virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1.

  • Trappin‐2/Elafin: a novel innate anti‐human Immunodeficiency Virus‐1 molecule of the human female reproductive tract
    Immunology, 2010
    Co-Authors: Mimi Ghosh, Zheng Shen, John V. Fahey, Susan Cu-uvin, Kenneth H. Mayer, Charles R. Wira
    Abstract:

    Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an Anti-Human Immunodeficiency Virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when Virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1.

Renate Kunert – One of the best experts on this subject based on the ideXlab platform.

  • improved Virus neutralization by plant produced anti hiv antibodies with a homogeneous β1 4 galactosylated n glycan profile
    Journal of Biological Chemistry, 2009
    Co-Authors: Richard Strasser, Alexandra Castilho, Johannes Stadlmann, Renate Kunert, Heribert Quendler, Pia Gattinger, Thomas W Rademacher, Friedrich Altmann, Lukas Mach, Herta Steinkellner
    Abstract:

    It is well established that proper N-glycosylation significantly influences the efficacy of monoclonal antibodies (mAbs). However, the specific immunological relevance of individual mAb-associated N-glycan structures is currently largely unknown, because of the heterogeneous N-glycan profiles of mAbs when produced in mammalian cells. Here we report on the generation of a plant-based expression platform allowing the efficient production of mAbs with a homogeneous β1,4-galactosylated N-glycosylation structure, the major N-glycan species present on serum IgG. This was achieved by the expression of a highly active modified version of the human β1,4-galactosyltransferase in glycoengineered plants lacking plant-specific glycosylation. Moreover, we demonstrate that two Anti-Human Immunodeficiency Virus mAbs with fully β1,4-galactosylated N-glycans display improved Virus neutralization potency when compared with other glycoforms produced in plants and Chinese hamster ovary cells. These findings indicate that mAbs containing such homogeneous N-glycan structures should display improved in vivo activities. Our system, using expression of mAbs in tobacco plants engineered for post-translational protein processing, provides a new means of overcoming the two hurdles that limit the therapeutic use of Anti-Human Immunodeficiency Virus mAbs in global health initiatives, low biological potency and high production costs.

  • the broadly neutralizing anti human Immunodeficiency Virus type 1 4e10 monoclonal antibody is better adapted to membrane bound epitope recognition and blocking than 2f5
    Journal of Virology, 2008
    Co-Authors: Nerea Huarte, Renate Kunert, Maier Lorizate, Ruben Maeso, Rocio Arranz, Jose M Valpuesta, Jose L Nieva
    Abstract:

    The broadly neutralizing 2F5 and 4E10 monoclonal antibodies (MAbs) recognize epitopes within the membrane-proximal external region (MPER) that connects the human Immunodeficiency Virus type 1 (HIV-1) envelope gp41 ectodomain with the transmembrane anchor. By adopting different conformations that stably insert into the virion external membrane interface, such as helical structures, a conserved aromatic-rich sequence within the MPER is thought to participate in HIV-1-cell fusion. Recent experimental evidence suggests that the neutralizing activity of 2F5 and 4E10 might correlate with the MAbs’ capacity to recognize epitopes inserted into the viral membrane, thereby impairing MPER fusogenic activity. To gain new insights into the molecular mechanism underlying viral neutralization by these antibodies, we have compared the capacities of 2F5 and 4E10 to block the membrane-disorganizing activity of MPER peptides inserted into the surface bilayer of solution-diffusing unilamellar vesicles. Both MAbs inhibited leakage of vesicular aqueous contents (membrane permeabilization) and intervesicular lipid mixing (membrane fusion) promoted by MPER-derived peptides. Thus, our data support the idea that antibody binding to a membrane-inserted epitope may interfere with the function of the MPER during gp41-induced fusion. Antibody insertion into a cholesterol-containing, uncharged virion-like membrane is mediated by specific epitope recognition, and moreover, partitioning-coupled folding into a helix reduces the efficiency of 2F5 MAb binding to its epitope in the membrane. We conclude that the capacity to interfere with the membrane activity of conserved MPER sequences is best correlated with the broad neutralization of the 4E10 MAb.

  • comprehensive cross clade neutralization analysis of a panel of anti human Immunodeficiency Virus type 1 monoclonal antibodies
    Journal of Virology, 2004
    Co-Authors: James M Binley, Michael B. Zwick, Meng Wang, Gabriela Stiegler, Renate Kunert, Terri Wrin, Bette T Korber, Colombe Chappey, Susan Zollapazner, Hermann Katinger
    Abstract:

    Broadly neutralizing monoclonal antibodies (MAbs) are potentially important tools in human Immunodeficiency Virus type 1 (HIV-1) vaccine design. A few rare MAbs have been intensively studied, but we still have a limited appreciation of their neutralization breadth. Using a pseudoVirus assay, we evaluated MAbs from clade B-infected donors and a clade B HIV + plasma against 93 Viruses from diverse backgrounds. Anti-gp120 MAbs exhibited greater activity against clade B than non-B Viruses, whereas anti-gp41 MAbs exhibited broad interclade activity. Unexpectedly, MAb 4E10 (directed against the C terminus of the gp41 ectodomain) neutralized all 90 Viruses with moderate potency. MAb 2F5 (directed against an epitope adjacent to that of 4E10) neutralized 67% of isolates, but none from clade C. Anti-gp120 MAb b12 (directed against an epitope overlapping the CD4 binding site) neutralized 50% of Viruses, including some from almost every clade. 2G12 (directed against a high-mannose epitope on gp120) neutralized 41% of the Viruses, but none from clades C or E. MAbs to the gp120 V3 loop, including 447-52D, neutralized a subset of clade B Viruses (up to 45%) but infrequently neutralized other clades (≤7%). MAbs b6 (directed against the CD4 binding site) and X5 (directed against a CD4-induced epitope of gp120) neutralized only sensitive primary clade B Viruses. The HIV + plasma neutralized 70% of the Viruses, including some from all major clades. Further analysis revealed five neutralizing immunotypes that were somewhat associated with clades. As well as the significance for vaccine design, our data have implications for passive-immunization studies in countries where clade C Viruses are common, given that only MAbs b12 and 4E10 were effective against Viruses from this clade.

Peter D Kwong – One of the best experts on this subject based on the ideXlab platform.

  • structure and mechanistic analysis of the anti human Immunodeficiency Virus type 1 antibody 2f5 in complex with its gp41 epitope
    Journal of Virology, 2004
    Co-Authors: Gilad Ofek, Hermann Katinger, Min Tang, Anna Sambor, John R Mascola, Richard T Wyatt, Peter D Kwong
    Abstract:

    The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human Immunodeficiency Virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.2-A resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 A in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.