Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Dan H. Barouch; James B. Whitney; Brian Moldt; Florian Klein; Thiago Y. Oliveira; Jinyan Liu; Kathryn E. Stephenson; Hui Wen Chang; Karthik Shekhar; Sanjana Gupta; Joseph P. Nkolola; Michael S. Seaman; Kaitlin M. Smith; Erica N. Borducchi; Crystal Cabral; Jeffrey Y. Smith; Stephen Blackmore; Srisowmya Sanisetty; James R. Perry; Matthew Beck; Mark G. Lewis; William Rinaldi; Arup K. Chakraborty; Pascal Poignard; Michel C. Nussenzweig; Dennis R. Burton

doi:10.1038/nature12744

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Dan H. Barouch, James B. Whitney, Brian Moldt, Florian Klein, Thiago Y. Oliveira, Jinyan Liu, Kathryn E. Stephenson, Hui Wen Chang, Karthik Shekhar, Sanjana Gupta, Joseph P. Nkolola, Michael S. Seaman, Kaitlin M. Smith, Erica N. Borducchi, Crystal Cabral, Jeffrey Y. Smith, Stephen Blackmore, Srisowmya Sanisetty, James R. Perry, Matthew BeckMark G. Lewis, William Rinaldi, Arup K. Chakraborty, Pascal Poignard, Michel C. Nussenzweig, Dennis R. Burton

Research output: Contribution to journal › Article › peer-review

553 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

Original language	English
Pages (from-to)	224-228
Number of pages	5
Journal	Nature
Volume	503
Issue number	7475
DOIs	https://doi.org/10.1038/nature12744
State	Published - 14 Nov 2013
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements We thank A. Brinkman, M. Ferguson, C. Gittens, R. Geleziunas, R. Hamel, K. Kelly, J. Kramer, A. McNally, D. Montefiori, L. Nogueira, L. Parenteau, M. Pensiero, L. Peter, M. Shetty, D. Sok, K. Stanley, F. Stephens, W. Wagner, B. Walker, A. West and J. Yalley-Ogunro for advice, assistance and reagents. The SIVmac239 Gag peptide pool was obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the National Institutes of Health (AI055332, AI060354, AI078526, AI084794, AI095985, AI096040, AI10063, AI100148, AI100663); the Bill and Melinda Gates Foundation (OPP1033091, OPP1033115, OPP1040741, OPP1040753); the Ragon Institute of MGH, MIT, and Harvard; the Lundbeck Foundation; and the Stavros Niarchos Foundation. M.C.N. is a Howard Hughes Medical Institute investigator. M.C.N. and D.R.B. are co-inventors on patents covering the monoclonal antibodies used in the present study.

Funding

Acknowledgements We thank A. Brinkman, M. Ferguson, C. Gittens, R. Geleziunas, R. Hamel, K. Kelly, J. Kramer, A. McNally, D. Montefiori, L. Nogueira, L. Parenteau, M. Pensiero, L. Peter, M. Shetty, D. Sok, K. Stanley, F. Stephens, W. Wagner, B. Walker, A. West and J. Yalley-Ogunro for advice, assistance and reagents. The SIVmac239 Gag peptide pool was obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the National Institutes of Health (AI055332, AI060354, AI078526, AI084794, AI095985, AI096040, AI10063, AI100148, AI100663); the Bill and Melinda Gates Foundation (OPP1033091, OPP1033115, OPP1040741, OPP1040753); the Ragon Institute of MGH, MIT, and Harvard; the Lundbeck Foundation; and the Stavros Niarchos Foundation. M.C.N. is a Howard Hughes Medical Institute investigator. M.C.N. and D.R.B. are co-inventors on patents covering the monoclonal antibodies used in the present study.

Funders	Funder number
National Institutes of Health	AI100663, AI055332, AI084794, AI100148, AI10063, AI095985, AI060354, AI078526, AI096040
NIH Office of the Director	P40OD012217
Bill and Melinda Gates Foundation	OPP1033091, OPP1040741, OPP1040753, OPP1033115
Ragon Institute of MGH, MIT and Harvard
Lundbeckfonden
Stavros Niarchos Foundation

UN SDGs

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10.1038/nature12744

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Barouch, D. H., Whitney, J. B., Moldt, B., Klein, F., Oliveira, T. Y., Liu, J., Stephenson, K. E., Chang, H. W., Shekhar, K., Gupta, S., Nkolola, J. P., Seaman, M. S., Smith, K. M., Borducchi, E. N., Cabral, C., Smith, J. Y., Blackmore, S., Sanisetty, S., Perry, J. R., ... Burton, D. R. (2013). Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature, 503(7475), 224-228. https://doi.org/10.1038/nature12744

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title = "Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys",

abstract = "Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.",

author = "Barouch, {Dan H.} and Whitney, {James B.} and Brian Moldt and Florian Klein and Oliveira, {Thiago Y.} and Jinyan Liu and Stephenson, {Kathryn E.} and Chang, {Hui Wen} and Karthik Shekhar and Sanjana Gupta and Nkolola, {Joseph P.} and Seaman, {Michael S.} and Smith, {Kaitlin M.} and Borducchi, {Erica N.} and Crystal Cabral and Smith, {Jeffrey Y.} and Stephen Blackmore and Srisowmya Sanisetty and Perry, {James R.} and Matthew Beck and Lewis, {Mark G.} and William Rinaldi and Chakraborty, {Arup K.} and Pascal Poignard and Nussenzweig, {Michel C.} and Burton, {Dennis R.}",

note = "Funding Information: Acknowledgements We thank A. Brinkman, M. Ferguson, C. Gittens, R. Geleziunas, R. Hamel, K. Kelly, J. Kramer, A. McNally, D. Montefiori, L. Nogueira, L. Parenteau, M. Pensiero, L. Peter, M. Shetty, D. Sok, K. Stanley, F. Stephens, W. Wagner, B. Walker, A. West and J. Yalley-Ogunro for advice, assistance and reagents. The SIVmac239 Gag peptide pool was obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the National Institutes of Health (AI055332, AI060354, AI078526, AI084794, AI095985, AI096040, AI10063, AI100148, AI100663); the Bill and Melinda Gates Foundation (OPP1033091, OPP1033115, OPP1040741, OPP1040753); the Ragon Institute of MGH, MIT, and Harvard; the Lundbeck Foundation; and the Stavros Niarchos Foundation. M.C.N. is a Howard Hughes Medical Institute investigator. M.C.N. and D.R.B. are co-inventors on patents covering the monoclonal antibodies used in the present study.",

year = "2013",

month = nov,

day = "14",

doi = "10.1038/nature12744",

language = "אנגלית",

volume = "503",

pages = "224--228",

journal = "Nature",

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Barouch, DH, Whitney, JB, Moldt, B, Klein, F, Oliveira, TY, Liu, J, Stephenson, KE, Chang, HW, Shekhar, K, Gupta, S, Nkolola, JP, Seaman, MS, Smith, KM, Borducchi, EN, Cabral, C, Smith, JY, Blackmore, S, Sanisetty, S, Perry, JR, Beck, M, Lewis, MG, Rinaldi, W, Chakraborty, AK, Poignard, P, Nussenzweig, MC & Burton, DR 2013, 'Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys', Nature, vol. 503, no. 7475, pp. 224-228. https://doi.org/10.1038/nature12744

TY - JOUR

T1 - Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

AU - Barouch, Dan H.

AU - Whitney, James B.

AU - Moldt, Brian

AU - Klein, Florian

AU - Oliveira, Thiago Y.

AU - Liu, Jinyan

AU - Stephenson, Kathryn E.

AU - Chang, Hui Wen

AU - Shekhar, Karthik

AU - Gupta, Sanjana

AU - Nkolola, Joseph P.

AU - Seaman, Michael S.

AU - Smith, Kaitlin M.

AU - Borducchi, Erica N.

AU - Cabral, Crystal

AU - Smith, Jeffrey Y.

AU - Blackmore, Stephen

AU - Sanisetty, Srisowmya

AU - Perry, James R.

AU - Beck, Matthew

AU - Lewis, Mark G.

AU - Rinaldi, William

AU - Chakraborty, Arup K.

AU - Poignard, Pascal

AU - Nussenzweig, Michel C.

AU - Burton, Dennis R.

N1 - Funding Information: Acknowledgements We thank A. Brinkman, M. Ferguson, C. Gittens, R. Geleziunas, R. Hamel, K. Kelly, J. Kramer, A. McNally, D. Montefiori, L. Nogueira, L. Parenteau, M. Pensiero, L. Peter, M. Shetty, D. Sok, K. Stanley, F. Stephens, W. Wagner, B. Walker, A. West and J. Yalley-Ogunro for advice, assistance and reagents. The SIVmac239 Gag peptide pool was obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the National Institutes of Health (AI055332, AI060354, AI078526, AI084794, AI095985, AI096040, AI10063, AI100148, AI100663); the Bill and Melinda Gates Foundation (OPP1033091, OPP1033115, OPP1040741, OPP1040753); the Ragon Institute of MGH, MIT, and Harvard; the Lundbeck Foundation; and the Stavros Niarchos Foundation. M.C.N. is a Howard Hughes Medical Institute investigator. M.C.N. and D.R.B. are co-inventors on patents covering the monoclonal antibodies used in the present study.

PY - 2013/11/14

Y1 - 2013/11/14

N2 - Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

AB - Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

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ER -

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Abstract

Bibliographical note

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