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Pathogenesis and Immunity

Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody

Lauren M. Hook, John M. Lubinski, Ming Jiang, Michael K. Pangburn, Harvey M. Friedman
Lauren M. Hook
1Infectious Disease Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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John M. Lubinski
1Infectious Disease Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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Ming Jiang
1Infectious Disease Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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Michael K. Pangburn
2Department of Biochemistry, University of Texas Health Science Center, Tyler, Texas 75703
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Harvey M. Friedman
1Infectious Disease Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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  • For correspondence: hfriedma@mail.med.upenn.edu
DOI: 10.1128/JVI.80.8.4038-4046.2006
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  • FIG. 1.
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    FIG. 1.

    (A) Western blot analysis examining gC2 expression in HSV-2 wild-type- and gC2-null-infected cell extracts. The blot was probed with rabbit anti-gC2 antibody R81 or rabbit anti-VP5 as a loading control. (B to E) Neutralization of HSV-1 (NS) and HSV-2 (G, 333, and 2.12) wild-type and gC-null strains by NHS. Viruses were incubated with PBS as a control or NHS as the source of complement at the concentrations indicated for 1 h at 37°C. Results are expressed as PFU/ml (% of control) and were calculated as follows: (PFU with NHS/PFU with PBS) × 100. Results represent the mean titers ± standard deviations of four separate experiments for strain G and of three experiments for strains 333, 2.12, and NS. AUC comparing wild-type and gC-null viruses: P < 0.0001 for strain G, P < 0.002 for strain 333, P < 0.001 for strain 2.12, and P < 0.05 for strain NS.

  • FIG. 2.
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    FIG. 2.

    (A) Complement-mediated neutralization of HSV-1 and HSV-2 gC-null viruses does not require activation of the alternative complement pathway. The gC1-null and gC2-null viruses were incubated with 50% NHS or NHS treated with EDTA (NHS+EDTA) or EGTA (NHS+EGTA). Virus treated with PBS served as the control. Results shown represent mean titers ± standard deviations of three independent experiments. P < 0.02, NHS with PBS for NS-gC1null or G-gC2null. P values were not significant for EDTA- or EGTA-treated NHS versus PBS for NS-gC1null or G-gC2null. (B) Complement-mediated neutralization of the gC1-null and gC2-null viruses is not dependent upon activation of the mannan-binding lectin complement pathway. Neutralization assays were performed on gC1-null and gC2-null viruses incubated with PBS, PBS containing d-mannose, 50% NHS, or NHS treated with either d-mannose or sucrose. Results shown represent mean titers ± standard deviations of three independent experiments. P < 0.02, comparing virus incubated with PBS or PBS containing d-mannose with virus incubated with NHS or NHS treated with d-mannose or sucrose.

  • FIG. 3.
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    FIG. 3.

    (A) Total hemolytic complement activity of NHS, NHS depleted of C1q (C1q depleted), and C1q-depleted serum reconstituted with C1q (C1q depleted+C1q). EA were incubated with serum and the percentage of EA lysed was determined. (B) gC1-null and gC2-null viruses are neutralized by the classical complement pathway. Neutralization experiments were performed with 20% NHS that was C1q depleted or reconstituted. Results shown represent mean titers ± standard deviations of three independent experiments. P < 0.02, comparing heat-inactivated NHS and either NHS or C1q-restored serum for NS-gC1null and G-gC2null. In contrast, values are not significant, P = 0.23 and 0.86, comparing heat-inactivated NHS with C1q-depleted serum for NS-gC1null and G-gC2null, respectively.

  • FIG. 4.
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    FIG. 4.

    Neutralization of HSV-1 and HSV-2 gC-null viruses by NHS from four donors occurs in the absence of specific antibodies against HSV. Neutralization experiments were performed on virus incubated with PBS, heat-inactivated NHS (inactive NHS), or 20% NHS. The four serum samples are labeled 1 to 4. Results shown represent the mean titers ± standard deviations of three separate experiments. P was <0.001 for all four sera, comparing PBS with NHS for NS-gC1null, and P ranged from 0.006 to <0.001 for G-gC2null viruses. In contrast, values are not significant for PBS versus heat-inactivated NHS.

  • FIG. 5.
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    FIG. 5.

    Neutralization of HSV-1 and HSV-2 gC-null viruses is dependent upon C3 activation. Neutralization experiments were performed on virus treated with PBS, 20% NHS, or NHS treated with either inactive compstatin (NHS+Linear) or active compstatin (NHS+4W9A). Results represent mean titers ± standard deviations of four independent experiments for NS-gC1null and three independent experiments for G-gC2null. For both viruses, differences were significant between PBS and NHS (P < 0.01) and PBS and NHS treated with inactive compstatin (P < 0.05). However, no significant differences were detected between PBS and NHS treated with active compstatin.

  • FIG. 6.
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    FIG. 6.

    (A) Total hemolytic complement activity of NHS, NHS depleted of C5 (C5 depleted), and C5-restored serum (C5 depleted+C5). (B) Neutralization of gC1-null and gC2-null viruses requires the presence of C5. Virus was incubated with PBS, 20% NHS, 20% NHS depleted of C5 (C5 depleted), or C5-restored serum (C5 depleted+C5). Results are expressed as the mean titers ± standard deviations of four independent experiments for NS-gC1null and two for G-gC2null. P < 0.005 for both viruses, comparing NHS and C5-restored NHS with PBS. No significant differences were detected between PBS and C5-depleted NHS. (C) Total hemolytic complement activity of NHS, NHS depleted of C6 (C6 depleted), and C6-restored serum (C6 depleted+C6). (D) Neutralization of gC1-null or gC2-null virus is not dependent on the presence of C6. Neutralization assays were performed on virus treated with PBS, 20% NHS, C6-depleted NHS (C6 depleted), and C6-restored serum (C6 depleted+C6). The results represent the mean titers ± standard deviations of three independent experiments for NS-gC1null and seven experiments for G-gC2null. P < 0.01 for both viruses, comparing PBS with NHS, C6-depleted, and C6-reconstituted serum.

  • FIG. 7.
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    FIG. 7.

    (A) Total hemolytic complement activity using NHS and NHS depleted of IgM (IgM depleted). Hemolytic assays were performed using antibody-coated sheep erythrocytes to demonstrate an intact classical complement pathway in IgM-depleted serum. (B) Natural IgM antibody is required for neutralization of HSV-1 and HSV-2 gC-null viruses. The gC-null viruses were incubated with 20% NHS, heat-inactivated NHS (inactive NHS), 20% NHS depleted of IgM (IgM depleted), and IgM-restored serum (IgM depleted+IgM). The results shown represent the mean titers ± standard deviations of four independent experiments. P < 0.05, comparing IgM-depleted with reconstituted sera for NS-gC1null and G-gC2null. In contrast, values are not significant when comparing PBS with IgM-depleted serum for NS-gC1null and G-gC2null, P = 0.83 and 0.31, respectively. (C to F) ELISA detects natural IgM antibody binding to gC2-null virus. Heat-inactivated 20% NHS from four donors was serially diluted and added to microtiter wells coated with G-gC2null or control wells. The experiment was performed twice with similar results. The results of one experiment are shown.

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Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody
Lauren M. Hook, John M. Lubinski, Ming Jiang, Michael K. Pangburn, Harvey M. Friedman
Journal of Virology Mar 2006, 80 (8) 4038-4046; DOI: 10.1128/JVI.80.8.4038-4046.2006

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Herpes Simplex Virus Type 1 and 2 Glycoprotein C Prevents Complement-Mediated Neutralization Induced by Natural Immunoglobulin M Antibody
Lauren M. Hook, John M. Lubinski, Ming Jiang, Michael K. Pangburn, Harvey M. Friedman
Journal of Virology Mar 2006, 80 (8) 4038-4046; DOI: 10.1128/JVI.80.8.4038-4046.2006
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KEYWORDS

Antibodies, Viral
Complement System Proteins
Immunoglobulin M
Viral Envelope Proteins

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