Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection

Matthew S. Parsons, Sarah B Lloyd, Wen Shi Lee, Anne B. Kristensen, Thakshila H Amarasena, Rob J. Center, Brandon F. Keele, Jeffrey D Lifson, Celia C. La Branche, David Montefiori, Bruce D. Wine, P. Mark Hogarth, Kristine M. Swiderek, Vanessa Venturi, Miles Philip Davenport, Stephen J. Kent

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIVSF162P3-infected splenocytes. All five controls had high viremia 1week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 mg/ml by 1 week after infusion and was well below 1 mg/ml (range, <0.1 to 0.8 mg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral bloodmononuclear cells (PBMCs) stored at weeks 1 to 4 fromthe animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cellassociated virus.

Original languageEnglish
Article numberaaf1483
Number of pages12
JournalScience Translational Medicine
Volume9
Issue number402
DOIs
Publication statusPublished - 9 Aug 2017

Cite this

Parsons, M. S., Lloyd, S. B., Lee, W. S., Kristensen, A. B., Amarasena, T. H., Center, R. J., ... Kent, S. J. (2017). Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection. Science Translational Medicine, 9(402), [aaf1483]. https://doi.org/10.1126/scitranslmed.aaf1483
Parsons, Matthew S. ; Lloyd, Sarah B ; Lee, Wen Shi ; Kristensen, Anne B. ; Amarasena, Thakshila H ; Center, Rob J. ; Keele, Brandon F. ; Lifson, Jeffrey D ; La Branche, Celia C. ; Montefiori, David ; Wine, Bruce D. ; Hogarth, P. Mark ; Swiderek, Kristine M. ; Venturi, Vanessa ; Davenport, Miles Philip ; Kent, Stephen J. / Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection. In: Science Translational Medicine. 2017 ; Vol. 9, No. 402.
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abstract = "Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIVSF162P3-infected splenocytes. All five controls had high viremia 1week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 mg/ml by 1 week after infusion and was well below 1 mg/ml (range, <0.1 to 0.8 mg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral bloodmononuclear cells (PBMCs) stored at weeks 1 to 4 fromthe animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cellassociated virus.",
author = "Parsons, {Matthew S.} and Lloyd, {Sarah B} and Lee, {Wen Shi} and Kristensen, {Anne B.} and Amarasena, {Thakshila H} and Center, {Rob J.} and Keele, {Brandon F.} and Lifson, {Jeffrey D} and {La Branche}, {Celia C.} and David Montefiori and Wine, {Bruce D.} and Hogarth, {P. Mark} and Swiderek, {Kristine M.} and Vanessa Venturi and Davenport, {Miles Philip} and Kent, {Stephen J.}",
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Parsons, MS, Lloyd, SB, Lee, WS, Kristensen, AB, Amarasena, TH, Center, RJ, Keele, BF, Lifson, JD, La Branche, CC, Montefiori, D, Wine, BD, Hogarth, PM, Swiderek, KM, Venturi, V, Davenport, MP & Kent, SJ 2017, 'Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection' Science Translational Medicine, vol. 9, no. 402, aaf1483. https://doi.org/10.1126/scitranslmed.aaf1483

Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection. / Parsons, Matthew S.; Lloyd, Sarah B; Lee, Wen Shi; Kristensen, Anne B.; Amarasena, Thakshila H; Center, Rob J.; Keele, Brandon F.; Lifson, Jeffrey D; La Branche, Celia C.; Montefiori, David; Wine, Bruce D.; Hogarth, P. Mark; Swiderek, Kristine M.; Venturi, Vanessa; Davenport, Miles Philip; Kent, Stephen J.

In: Science Translational Medicine, Vol. 9, No. 402, aaf1483, 09.08.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Parsons, Matthew S.

AU - Lloyd, Sarah B

AU - Lee, Wen Shi

AU - Kristensen, Anne B.

AU - Amarasena, Thakshila H

AU - Center, Rob J.

AU - Keele, Brandon F.

AU - Lifson, Jeffrey D

AU - La Branche, Celia C.

AU - Montefiori, David

AU - Wine, Bruce D.

AU - Hogarth, P. Mark

AU - Swiderek, Kristine M.

AU - Venturi, Vanessa

AU - Davenport, Miles Philip

AU - Kent, Stephen J.

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N2 - Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIVSF162P3-infected splenocytes. All five controls had high viremia 1week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 mg/ml by 1 week after infusion and was well below 1 mg/ml (range, <0.1 to 0.8 mg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral bloodmononuclear cells (PBMCs) stored at weeks 1 to 4 fromthe animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cellassociated virus.

AB - Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission. To evaluate whether a BnAb can prevent infection after cell-associated viral challenge, we infused pigtail macaques with PGT121 or an isotype control and challenged animals 1 hour later intravenously with SHIVSF162P3-infected splenocytes. All five controls had high viremia 1week after challenge. Three of six PGT121-infused animals were completely protected, two of six animals had a 1-week delay in onset of high viremia, and one animal had a 7-week delay in onset of viremia. The infused antibody had decayed on average to 2.0 mg/ml by 1 week after infusion and was well below 1 mg/ml (range, <0.1 to 0.8 mg/ml) by 8 weeks. The animals with a 1-week delay before high viremia had relatively lower plasma concentrations of PGT121. Transfer of 22 million peripheral bloodmononuclear cells (PBMCs) stored at weeks 1 to 4 fromthe animal with the 7-week delayed onset of viremia into uninfected macaques did not initiate infection. Our results show that HIV-1-specific neutralizing antibodies have partial efficacy against cell-associated virus exposure in macaques. We conclude that sustaining high concentrations of bioavailable BnAb is important for protecting against cellassociated virus.

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