Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission

Xiao L. Chang; Gabriela M. Webb; Helen L. Wu; Justin M. Greene; Shaheed Abdulhaqq; Katherine B. Bateman; Jason S. Reed; Cleiton Pessoa; Whitney C. Weber; Nicholas Maier; Glen M. Chew; Roxanne M. Gilbride; Lina Gao; Rebecca Agnor; Travis Giobbi; Jeffrey Torgerson; Don Siess; Nicole Burnett; Miranda Fischer; Oriene Shiel; Cassandra Moats; Bruce Patterson; Kush Dhody; Scott Kelly; Nader Pourhassan; Diogo M. Magnani; Jeremy Smedley; Benjamin N. Bimber; Nancy L. Haigwood; Scott G. Hansen; Timothy R. Brown; Lishomwa C. Ndhlovu; Jonah B. Sacha

doi:10.1038/s41467-021-23697-6

Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission

Xiao L. Chang
, Gabriela M. Webb
, Helen L. Wu
, Justin M. Greene
, Shaheed Abdulhaqq
, Katherine B. Bateman
, Jason S. Reed
, Cleiton Pessoa
, Whitney C. Weber
, Nicholas Maier
, Glen M. Chew
, Roxanne M. Gilbride
, Lina Gao
, Rebecca Agnor
, Travis Giobbi
, Jeffrey Torgerson
, Don Siess
, Nicole Burnett
, Miranda Fischer
, Oriene Shiel

Cassandra Moats, Bruce Patterson, Kush Dhody, Scott Kelly, Nader Pourhassan, Diogo M. Magnani, Jeremy Smedley, Benjamin N. Bimber, Nancy L. Haigwood, Scott G. Hansen, Timothy R. Brown, Lishomwa C. Ndhlovu, Jonah B. Sacha

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

21 Scopus citations

Abstract

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIV_SF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.

Original language	English (US)
Article number	3343
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23697-6
State	Published - Dec 1 2021

Funding

We thank Nancy Miller for providing the in vivo characterized SHIVSF162P3 challenge stock and the dedicated animal care staff at ONPRC. We acknowledge the contribution of the Hawaii Center for AIDS, Director, Dr. Cecilia Shikuma and the Leukapharesis team at Queens Medical Center for support and commitment in specimen sampling from the study participant. Reagents used in these studies were provided by the NIH Nonhuman Primate Reagent Resource. The following reagent was obtained through the AIDS Reagent Program, Division of AIDS, NIAID, NIH: human IL-2 from La Roche and the HIV-1 60 International Isolate Panel. We acknowledge the macaques that contributed to this study. This manuscript is dedicated to Timothy Ray Brown, who inspired, supported, and materially contributed to this research. Macaque icons used in Fig. 2a were created on BioRender.com. This work is supported by National Institute of Allergy and Infectious Diseases (NIAID) grants R01 AI129703, R01 AI54559, and R21 AI54559 to J.B.S., K01 OD026561 to J.M.G., U24 AI126683 to D.M.M., and the Oregon National Primate Research Center Core grant P51 OD011092 from the National Institutes of Health, Office of the Director.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute of Allergy and Infectious Diseases	R21 AI54559, U24AI126683, K01 OD026561, R01 AI129703
Office of the Director
Oregon National Primate Research Center	P51 OD011092

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Chang, X. L., Webb, G. M., Wu, H. L., Greene, J. M., Abdulhaqq, S., Bateman, K. B., Reed, J. S., Pessoa, C., Weber, W. C., Maier, N., Chew, G. M., Gilbride, R. M., Gao, L., Agnor, R., Giobbi, T., Torgerson, J., Siess, D., Burnett, N., Fischer, M., ... Sacha, J. B. (2021). Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission. Nature communications, 12(1), Article 3343. https://doi.org/10.1038/s41467-021-23697-6

Chang, XL, Webb, GM, Wu, HL, Greene, JM, Abdulhaqq, S, Bateman, KB, Reed, JS, Pessoa, C, Weber, WC, Maier, N, Chew, GM, Gilbride, RM, Gao, L, Agnor, R, Giobbi, T, Torgerson, J, Siess, D, Burnett, N, Fischer, M, Shiel, O, Moats, C, Patterson, B, Dhody, K, Kelly, S, Pourhassan, N, Magnani, DM, Smedley, J, Bimber, BN, Haigwood, NL, Hansen, SG, Brown, TR, Ndhlovu, LC & Sacha, JB 2021, 'Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission', Nature communications, vol. 12, no. 1, 3343. https://doi.org/10.1038/s41467-021-23697-6

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abstract = "In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIVSF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into na{\"i}ve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.",

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Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission

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