HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Johannes F. Scheid; Joshua A. Horwitz; Yotam Bar-On; Edward F. Kreider; Ching Lan Lu; Julio C.C. Lorenzi; Anna Feldmann; Malte Braunschweig; Lilian Nogueira; Thiago Oliveira; Irina Shimeliovich; Roshni Patel; Leah Burke; Yehuda Z. Cohen; Sonya Hadrigan; Allison Settler; Maggi Witmer-Pack; Anthony P. West; Boris Juelg; Tibor Keler; Thomas Hawthorne; Barry Zingman; Roy M. Gulick; Nico Pfeifer; Gerald H. Learn; Michael S. Seaman; Pamela J. Bjorkman; Florian Klein; Sarah J. Schlesinger; Bruce D. Walker; Beatrice H. Hahn; Michel C. Nussenzweig; Marina Caskey

doi:10.1038/nature18929

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Johannes F. Scheid, Joshua A. Horwitz, Yotam Bar-On, Edward F. Kreider, Ching Lan Lu, Julio C.C. Lorenzi, Anna Feldmann, Malte Braunschweig, Lilian Nogueira, Thiago Oliveira, Irina Shimeliovich, Roshni Patel, Leah Burke, Yehuda Z. Cohen, Sonya Hadrigan, Allison Settler, Maggi Witmer-Pack, Anthony P. West, Boris Juelg, Tibor KelerThomas Hawthorne, Barry Zingman, Roy M. Gulick, Nico Pfeifer, Gerald H. Learn, Michael S. Seaman, Pamela J. Bjorkman, Florian Klein, Sarah J. Schlesinger, Bruce D. Walker, Beatrice H. Hahn, Michel C. Nussenzweig, Marina Caskey

Medicine

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357 Scopus citations

Abstract

Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.

Original language	English (US)
Pages (from-to)	556-560
Number of pages	5
Journal	Nature
Volume	535
Issue number	7613
DOIs	https://doi.org/10.1038/nature18929
State	Published - Jul 28 2016

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Scheid, J. F., Horwitz, J. A., Bar-On, Y., Kreider, E. F., Lu, C. L., Lorenzi, J. C. C., Feldmann, A., Braunschweig, M., Nogueira, L., Oliveira, T., Shimeliovich, I., Patel, R., Burke, L., Cohen, Y. Z., Hadrigan, S., Settler, A., Witmer-Pack, M., West, A. P., Juelg, B., ... Caskey, M. (2016). HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature, 535(7613), 556-560. https://doi.org/10.1038/nature18929

Scheid, JF, Horwitz, JA, Bar-On, Y, Kreider, EF, Lu, CL, Lorenzi, JCC, Feldmann, A, Braunschweig, M, Nogueira, L, Oliveira, T, Shimeliovich, I, Patel, R, Burke, L, Cohen, YZ, Hadrigan, S, Settler, A, Witmer-Pack, M, West, AP, Juelg, B, Keler, T, Hawthorne, T, Zingman, B, Gulick, RM, Pfeifer, N, Learn, GH, Seaman, MS, Bjorkman, PJ, Klein, F, Schlesinger, SJ, Walker, BD, Hahn, BH, Nussenzweig, MC & Caskey, M 2016, 'HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption', Nature, vol. 535, no. 7613, pp. 556-560. https://doi.org/10.1038/nature18929

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title = "HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption",

abstract = "Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.",

author = "Scheid, {Johannes F.} and Horwitz, {Joshua A.} and Yotam Bar-On and Kreider, {Edward F.} and Lu, {Ching Lan} and Lorenzi, {Julio C.C.} and Anna Feldmann and Malte Braunschweig and Lilian Nogueira and Thiago Oliveira and Irina Shimeliovich and Roshni Patel and Leah Burke and Cohen, {Yehuda Z.} and Sonya Hadrigan and Allison Settler and Maggi Witmer-Pack and West, {Anthony P.} and Boris Juelg and Tibor Keler and Thomas Hawthorne and Barry Zingman and Gulick, {Roy M.} and Nico Pfeifer and Learn, {Gerald H.} and Seaman, {Michael S.} and Bjorkman, {Pamela J.} and Florian Klein and Schlesinger, {Sarah J.} and Walker, {Bruce D.} and Hahn, {Beatrice H.} and Nussenzweig, {Michel C.} and Marina Caskey",

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T1 - HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

AU - Scheid, Johannes F.

AU - Horwitz, Joshua A.

AU - Bar-On, Yotam

AU - Kreider, Edward F.

AU - Lu, Ching Lan

AU - Lorenzi, Julio C.C.

AU - Feldmann, Anna

AU - Braunschweig, Malte

AU - Nogueira, Lilian

AU - Oliveira, Thiago

AU - Shimeliovich, Irina

AU - Patel, Roshni

AU - Burke, Leah

AU - Cohen, Yehuda Z.

AU - Hadrigan, Sonya

AU - Settler, Allison

AU - Witmer-Pack, Maggi

AU - West, Anthony P.

AU - Juelg, Boris

AU - Keler, Tibor

AU - Hawthorne, Thomas

AU - Zingman, Barry

AU - Gulick, Roy M.

AU - Pfeifer, Nico

AU - Learn, Gerald H.

AU - Seaman, Michael S.

AU - Bjorkman, Pamela J.

AU - Klein, Florian

AU - Schlesinger, Sarah J.

AU - Walker, Bruce D.

AU - Hahn, Beatrice H.

AU - Nussenzweig, Michel C.

AU - Caskey, Marina

PY - 2016/7/28

Y1 - 2016/7/28

N2 - Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.

AB - Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.

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HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Abstract

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