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Pathogenesis and Immunity

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

D. Noah Sather, Jakob Armann, Lance K. Ching, Angeliki Mavrantoni, George Sellhorn, Zachary Caldwell, Xuesong Yu, Blake Wood, Steve Self, Spyros Kalams, Leonidas Stamatatos
D. Noah Sather
1Seattle Biomedical Research Institute, Seattle, Washington 98109
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Jakob Armann
1Seattle Biomedical Research Institute, Seattle, Washington 98109
2Ludwig-Maximilians-University, Munich, Germany
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Lance K. Ching
1Seattle Biomedical Research Institute, Seattle, Washington 98109
3Department of Global Health, University of Washington, Seattle, Washington 98109
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Angeliki Mavrantoni
1Seattle Biomedical Research Institute, Seattle, Washington 98109
4Department of Molecular Biology and Genetics, Democritus University of Thrace, Thrace, Greece
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George Sellhorn
1Seattle Biomedical Research Institute, Seattle, Washington 98109
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Zachary Caldwell
1Seattle Biomedical Research Institute, Seattle, Washington 98109
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Xuesong Yu
5Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
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Blake Wood
5Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
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Steve Self
5Statistical Center for HIV/AIDS Research & Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
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Spyros Kalams
6Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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Leonidas Stamatatos
1Seattle Biomedical Research Institute, Seattle, Washington 98109
3Department of Global Health, University of Washington, Seattle, Washington 98109
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  • For correspondence: leo.stamatatos@sbri.org
DOI: 10.1128/JVI.02036-08
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  • FIG. 1.
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    FIG. 1.

    Cross-NAb responses in the Vanderbilt cohort. Values represent the plasma dilution at which 50% neutralization was detected. Plasma samples were tested in a dilution range of 1:20 to 1:2,560. Gray-shaded boxes indicate the neutralization of a particular isolate by the indicated plasma sample. (-), 50% neutralization was not recorded at a 1:20 plasma dilution; ETI, estimated time of infection; EY, estimated time (in years) since infection that the plasma sample was obtained and tested. Values listed in the % breadth column are the percentages of the isolates tested that each plasma neutralized (i.e., the breadth of neutralization). Clade B viruses that are part of a panel of viruses created to evaluate the anti-HIV neutralizing responses elicited during infection or during immunization (17) are indicated by an asterisk. Cl. A, clade A.

  • FIG. 2.
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    FIG. 2.

    Cross-NAb responses in the UW/CFAR cohort. Values represent the plasma dilution at which 50% neutralization was detected. Plasma samples were tested in a dilution range of 1:20 to 1:2,560. Gray-shaded boxes indicate neutralization of a particular isolate by the indicated plasma sample. (-), 50% neutralization was not recorded at a 1:20 plasma dilution. The times of infection for this cohort are unknown. TO, time point (in years) after enrollment at which the plasmas were collected and tested for neutralizing activity. Values listed in the breadth column are the percentages of the isolates tested that each plasma neutralized (i.e., the breadth of neutralization). Clade B viruses that are part of a panel of viruses created to evaluate the anti-HIV neutralizing responses elicited during infection or during immunization (17) are indicated by an asterisk. Cl. A, clade A.

  • FIG. 3.
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    FIG. 3.

    Peptide competition neutralization assays. (A to F) Serially diluted plasmas were preincubated with the consensus clade B peptides corresponding to various regions of the HIV Env before use in neutralization assays against the primary isolate SF162. (G) Competition of plasma VC10028 using the 4E10 and a scrambled 4E10 peptide with the JRFL virus. A reduction in neutralization after preincubation with peptides indicates that the plasma contains NAbs directed at the corresponding regions of the HIV Env. The breadth of neutralization is indicated in parenthesis after each plasma's code. Ab, antibody.

  • FIG. 4.
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    FIG. 4.

    (A) Contribution of anti-V1, anti-V2, or anti-V3 antibody to the plasma's neutralizing activity against SF162. (B) Contribution of V3-directed antibodies to the plasma's overall neutralizing activity against six primary HIV-1 isolates. The values indicate the percent reduction of the plasma's neutralizing activity against the indicated isolates following the preincubation of the plasma with the indicated peptides. TSI, the time since infection (in years) that plasmas were collected in the Vanderbilt cohort; (-), no reduction in the plasma's neutralizing activity was recorded; ND, the plasma has no neutralizing activity against the indicated virus.

  • FIG. 5.
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    FIG. 5.

    Contribution of anti-CD4-BS antibodies to plasma-neutralizing activities. Plasmas were incubated with beads coated with either WT gp120 or gp120 with a mutated CD4-BS. The flowthrough and the eluted antibodies were tested for neutralizing activity against HIV. (A and B) Sample from patient VC10042; (C and D) sample from patient VC10014; (E and F) sample from patient CC1161; (G and H) sample from VC10002. Flowthroughs (A, C, E, and G) and eluted antibodies (B, D, F and H) are shown. Nondepleted, neutralization curves obtained with unadsorbed plasmas; WT depleted, plasma flowthroughs from WT gp120; BS-mutant depleted, plasma flowthroughs from the CD4-BS mutant gp120.

  • FIG. 6.
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    FIG. 6.

    Presence of 2F5- or 4E10-like NAbs in plasma. (A) Values indicate the percent reduction in each plasma's neutralizing activity against SF162 following the preincubation of plasma with either r2F5 or 4E10 peptide. (B) The percent reduction in each plasma's neutralizing activity against six primary isolates following the preincubation of the plasma with the 4E10 peptide. (-), no reduction was recorded; ND, the plasma does not neutralize the indicated virus.

  • FIG. 7.
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    FIG. 7.

    Detection of anti-CD4-BS antibodies in HIV+ plasmas. (A) Recognition of WT gp120 and CD4-BS mutant gp120 by specific anti-gp120 MAbs. IgG-CD4, chimeric molecule that binds to the CD4-BS of gp120; b12, an antibody that binds to an epitope that overlaps the CD4-BS; 447D, anti-V3 antibody; 2G12, an antibody that binds to a complex conformational epitope on gp120 formed by mannose residues. Closed symbols denote WT gp120 and open symbols denote CD4-BS mutant gp120 as the antigen in the ELISA. (B) Recognition of WT gp120 by the flowthroughs from WT gp120 and the CD4-BS mutant gp120 shown for seven HIV+ subjects with distinct breadths of NAb responses. Non Dep, relative end-point ELISA antibody titers in plasma; gp120, flowthrough following plasma's mixing with beads coated with WT gp120; and gp120bs, flowthrough following plasma's mixing with beads coated with CD4-BS mutant gp120. Arrows indicate the relative titers of antibodies binding to the CD4-BS of gp120.

Tables

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  • TABLE 1.

    Factors correlated with the breadth of cross-NAb responses in plasma for the combined cohorts

    CovariateEstimateUnivariate model result
    95% CIP valuea
    Avg avidity1.721.53, 1.94<0.001
    Avg log(VL)1.911.56, 2.34<0.001
    Avg IgG2.351.84, 3.01<0.001
    Avg log(CD4)0.190.07, 0.490.001
    • ↵ a All P values were statistically significant.

  • TABLE 2.

    Factors correlated with the breadth of cross-NAb responses in plasma for the Vanderbilt cohort

    CovariatesEstimateModel resultsa
    UnivariateMultivariate
    95% CIP value95% CIP value
    Duration of Infection1.091.05, 1.13 <0.001 1.03, 1.12 0.001
    Average Avidity1.931.63, 2.29 <0.001 1.44, 2.06 <0.001
    Average log(viral load)1.991.44, 2.76 <0.001 1.24, 2.47 0.002
    Average IgG2.301.75, 3.01 <0.001
    Average log(CD4)0.320.09, 1.160.084
    Average log(CD8)20.896.60, 66.04 <0.001
    • ↵ a Statistically significant P values are in boldface.

  • TABLE 3.

    Contribution of anti-CD4-BS antibodies to the cross-neutralizing activity of plasmasa

    Subject (% breadth)IsolatePlasma% Neutralization of flowthroughIC50 (μg/ml) of eluted antibodies
    WT gp120BS gp120WT gp120BS gp120
    VC10042 (100)YU2 100 (-) 100 1.2(-)
    QH0692 90 19 100 1.9(-)
    TORNO 92 15 90 6.6(-)
    JRFL 99 10 99 1.5(-)
    VC10014 (79)YU2 92 (-)156.58.1
    QH0692 52 122814.519.1
    TORNO 70 254512.314.6
    JRFL 95 5357.310.3
    CC1161 (84)YU2 89 37 65 1.4(-)
    QH0692 73 44 62 6.1(-)
    TORNO 95 82 81 1.83.8
    JRFL 98 88 89 3.91.8
    VC10002 (32)YU240(-)(-)(-)(-)
    QH0692 85 53 60 7.210.8
    TORNO 72 52 57 8.915
    JRFL 90 47 55 8.613.4
    CC1508 (95)YU2 95 91 92 (-)(-)
    QH0692 98 68 75 13.614.2
    TORNO 90 82 86 8.113.4
    JRFL 100 100 99 (-)(-)
    VC20013 (63)YU2271222(-)(-)
    QH0692 78 78 72 (-)(-)
    TORNO 73 73 72 (-)(-)
    JRFL 70 63 58 8.49.7
    VC20011 (5)YU2(-)(-)(-)(-)(-)
    QH0692(-)(-)(-)(-)(-)
    TORNO(-)(-)(-)(-)(-)
    JRFL(-)(-)(-)(-)(-)
    • ↵ a The anti-HIV-neutralizing activities of the flowthrough from the WT gp120 and the CD4-BS mutant gp120 (BS gp120) and those of the antibodies eluted from the WT gp120 and CD4-BS mutant gp120 were determined as discussed in Materials and Methods. For the plasma and flowthroughs, the percent neutralization at a 1:50 dilution is shown. Significant neutralization (≥50%) is shown in boldface. For the eluted antibodies, the IC50s are shown. (-), neutralizing activity (50% neutralization) against the indicated virus was not recorded at a 1:50 dilution. The overall breadth of neutralization for each plasma is shown under each code identifier.

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Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection
D. Noah Sather, Jakob Armann, Lance K. Ching, Angeliki Mavrantoni, George Sellhorn, Zachary Caldwell, Xuesong Yu, Blake Wood, Steve Self, Spyros Kalams, Leonidas Stamatatos
Journal of Virology Dec 2008, 83 (2) 757-769; DOI: 10.1128/JVI.02036-08

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Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection
D. Noah Sather, Jakob Armann, Lance K. Ching, Angeliki Mavrantoni, George Sellhorn, Zachary Caldwell, Xuesong Yu, Blake Wood, Steve Self, Spyros Kalams, Leonidas Stamatatos
Journal of Virology Dec 2008, 83 (2) 757-769; DOI: 10.1128/JVI.02036-08
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KEYWORDS

HIV Antibodies
HIV Infections
HIV-1

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