Research ArticleHIV

Protection against a mixed SHIV challenge by a broadly neutralizing antibody cocktail

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Science Translational Medicine  20 Sep 2017:
Vol. 9, Issue 408, eaao4235
DOI: 10.1126/scitranslmed.aao4235
  • Fig. 1. SHIV-SF162P3 escape from 10-1074 in rhesus monkeys.

    Log plasma viral RNA copies per mililliter in chronically SHIV-SF162P3–infected rhesus monkeys after infusion with a single dose of 10-1074 (10 mg/kg) or PGT121 (10 mg/kg) on day 0. Detection limit is 50 copies/ml. mAb, monoclonal antibody.

  • Fig. 2. Analysis of SHIV env sequences in 10-1074–treated animals.

    Viral sequences by SGA of plasma viruses before and after 10-1074 administration. Amino acid residues that were detected at days 14 and 42 are highlighted in red.

  • Fig. 3. Frequencies of amino acids at critical PGT121 and 10-1074 contact sites in the SHIV-SF162P3 challenge stock.

    (A) “O” indicates an Asn that is part of a PNGS (positions 295, 301, and 332). The critical N332 and S334 residues are circled in red. aa, amino acid. (B) PGT121 and 10-1074 neutralization potency of SHIV-SF162P3 (wild-type) and SHIV-SF162P3 containing an N332A mutation.

  • Fig. 4. Complementarity of neutralization profiles of PGDM1400 and PGT121 against HIV-1.

    (A) IC80 titers for PGDM1400, PGT121, and the combination of PGT121 + PGDM1400 against a panel of 118 multiclade viruses. IC80 titers are shown as a heatmap with viruses represented in rows. Dark red indicates more potent neutralization, and light yellow indicates less potent neutralization. Blue indicates IC80 neutralization titers >50 μg/ml. The IC80 titers in the combination reflect the concentration of each bNAb. (B) IC80 breadth-potency plots for PGDM1400, PGT121, and the combination of PGT121 + PGDM1400. (C) IC80 titers for PGDM1400, PGT121, and the combination of PGT121 + PGDM1400 for pseudoviruses from clades A, B, C, and CRF01. Bold horizontal lines represent medians, and thin horizontal lines are 25th and 75th percentiles. The percentage of viruses with IC80 titers >50 μg/ml is shown on the top of each panel. P values reflect Fisher’s exact tests. thr, threshold; CRF01, circulating recombinant form 01.

  • Fig. 5. Protective efficacy of the combination of PGT121 + PGDM1400 against a mixed SHIV challenge in rhesus monkeys.

    Five animals per group received an intravenous single dose of PGDM1400, PGT121, the combination of PGT121 + PGDM1400, or saline (Sham) before being rectally challenged with a high dose of both SHIV-SF162P3 and SHIV-325c. Log plasma viral RNA copies per milliliter after mixed challenge with SHIV-SF162P3 and SHIV-325c. Red line indicates median values. Detection limit is 50 copies/ml.

  • Fig. 6. Analysis of SHIV env sequences in breakthrough infections.

    Maximum likelihood tree depicting SHIV env sequences by SGA of plasma viruses at weeks 2 to 6 after challenge. The sequences of the challenge stock SHIVs are highlighted in green.

  • Fig. 7. Intrapatient variation in key contact signatures for PGDM1400 and PGT121.

    Logo plots of viral sequence diversity in the key PGDM1400 and PGT121 contact sites (figs. S8 to S10) in 10 HIV-1–infected individuals for whom >150 full-length env sequences were available in the Los Alamos Sequence Database. The subject ID is indicated above each plot. The x axis indicates the amino acid position based on HXB2 numbering. The y axis indicates the probability of an amino acid at this location. O indicates an Asn that is part of a PNGS. Blue reflects sensitivity signatures, red reflects resistance signatures, and black reflects no statistically significant associated with antibody sensitivity.

  • Table 1. IC50 and IC80 neutralization titers (in μg/ml) of PGT121 and PGDM1400 against SHIV-SF162P3 and SHIV-325c.
    AntibodySHIV-SF162P3SHIV-325c
    IC50IC80IC50IC80
    PGDM1400>50>500.0150.061
    PGT1210.0850.17>50>50
  • Table 2. Number of SHIV strain–specific single-genome sequences in the animals that experienced breakthrough infection.
    GroupMonkeyTotal SGA sequences
    SHIV-SF162P3SHIV-325c
    PGT121 aloneA12R05308
    A12L121011
    A12L129015
    T51602
    T52906
    PGDM1400 aloneA12L110180
    A12L125330
    A12L088240
    T521350
    T535360
    ShamA12R029250
    A12R030270
    A12R037430
    T522360
    T536360

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/9/408/eaao4235/DC1

    Fig. S1. Analysis of SHIV env sequences in PGT121-treated animals.

    Fig. S2. Complementarity of complete neutralization profiles of PGDM1400 and PGT121 against HIV-1.

    Fig. S3. Serum concentration of PGDM1400 and PGT121 in antibody-treated animals by ELISA.

    Fig. S4. Serum concentration of PGDM1400 and PGT121 in antibody-treated animals by TZM-bl NAb assays.

    Fig. S5. Comparison of ELISA and TZM-bl neutralization assays for evaluating pharmacokinetics of PGDM1400 and PGT121.

    Fig. S6. Protective efficacy as measured by SHIV-SF162P3–specific viral loads.

    Fig. S7. Protective efficacy as measured by SHIV-325c–specific viral loads.

    Fig. S8. Structural modeling of PGT121 and PGDM1400 contact sites.

    Fig. S9. Clade diversity of key signature residues for PGDM1400.

    Fig. S10. Clade diversity of key signature residues for PGT121.

    Table S1. Intrapatient variation in key contact signatures for PGDM140 and PGT121.

  • Supplementary Material for:

    Protection against a mixed SHIV challenge by a broadly neutralizing antibody cocktail

    Boris Julg, Po-Ting Liu, Kshitij Wagh, William M. Fischer, Peter Abbink, Noe B. Mercado, James B. Whitney, Joseph P. Nkolola, Katherine McMahan, Lawrence J. Tartaglia, Erica N. Borducchi, Shreeya Khatiwada, Megha Kamath, Jake A. LeSuer, Michael S. Seaman, Stephen D. Schmidt, John R. Mascola, Dennis R. Burton, Bette T. Korber, Dan H. Barouch*

    *Corresponding author. Email: dbarouch{at}bidmc.harvard.edu

    Published 20 September 2017, Sci. Transl. Med. 9, eaao4235 (2017)
    DOI: 10.1126/scitranslmed.aao4235

    This PDF file includes:

    • Fig. S1. Analysis of SHIV env sequences in PGT121-treated animals.
    • Fig. S2. Complementarity of complete neutralization profiles of PGDM1400 and PGT121 against HIV-1.
    • Fig. S3. Serum concentration of PGDM1400 and PGT121 in antibody-treated animals by ELISA.
    • Fig. S4. Serum concentration of PGDM1400 and PGT121 in antibody-treated animals by TZM-bl NAb assays.
    • Fig. S5. Comparison of ELISA and TZM-bl neutralization assays for evaluating pharmacokinetics of PGDM1400 and PGT121.
    • Fig. S6. Protective efficacy as measured by SHIV-SF162P3–specific viral loads.
    • Fig. S7. Protective efficacy as measured by SHIV-325c–specific viral loads.
    • Fig. S8. Structural modeling of PGT121 and PGDM1400 contact sites.
    • Fig. S9. Clade diversity of key signature residues for PGDM1400.
    • Fig. S10. Clade diversity of key signature residues for PGT121.
    • Table S1. Intrapatient variation in key contact signatures for PGDM140 and PGT121.

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