SIV monoclonal antibody administration spanning treatment interruption in macaques delays viral rebound and selects escape variants
Abstract
HIV-1 envelope broadly neutralizing antibodies represent a promising component of HIV-1 cure strategies. To evaluate the therapeutic efficacy of combination monoclonal antibodies (mAbs) in a rigorous nonhuman primate model, we tested different combinations of simian immunodeficiency virus (SIV) neutralizing mAbs in SIVmac251-infected rhesus macaques. Antiretroviral therapy-suppressed animals received anti-SIV mAbs targeting multiple Env epitopes spanning analytical treatment interruption (ATI) in 3 groups (n = 7 each): i) no mAb; ii) 4-mAb combination; and iii) 2-mAb combination. Each mAb was administered at 15 mg/kg, and both mAb-treated groups received ITS103.01, a highly potent CD4-binding site targeting antibody. mAb treatment delayed viral rebound, lowered rebound viremia setpoint and viral diversity, and extended animal lifespan. Compared to controls, for which viremia rebounded 2 wk following ATI, mAb infusion delayed rebound for both groups ( P = 0.0003). Animals that received the 4-mAb regimen rebounded 3 to 6 wk post-ATI while the 2-mAb regimen rebounded 5 to 22 wk post-ATI. Envelope escape mutations emerged in rebound virus of mAb-treated animals that abrogated neutralization by ITS103.01, the most potent in the cocktail. These data demonstrate in vivo antiviral activity of SIV mAbs in the context of ATI via immune pressure dominated by the most potent mAb and highlight their potential in adjunctive therapeutic studies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Hannah A. D. King
Daniel Brammer
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Eric Lewitus
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Christine M. Fennessey
Kimberly M. Manalang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Hannah R. Shrader
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Shayne Andrew
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Phillip Kuri
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Matthew Lind
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Phuc Pham
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Eric Sanders-Buell
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Hongjun Bai
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Rosemarie Mason
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Kaimei Song
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Elizabeth McCarthy
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Sabrina Helmold Hait
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
John-Paul Todd
Amarendra Pegu
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH
Kathryn E. Foulds
Jeffrey D. Lifson
Brandon F. Keele
Morgane Rolland
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Mario Roederer
Diane L. Bolton
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research