Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans1,2,3,4,5,6,7,8,9,10,11,12. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.
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We thank A. Peach and T. Lewis for determining plasma viral RNA loads, and K. Rice, R. Engel, R. Petros, and S. Fong for assisting in the maintenance of animals and performing procedures. We thank R. Fast for technical assistance with ultrasensitive viral load assays, and J. Brenchley for performing FACS analyses. We are indebted to Gilead Sciences for providing tenofovir and emtricitabine. The anti-CD8 mAbs, MT807R1 and CD8b255R1, were obtained from the National Institutes of Health (NIH) Nonhuman Primate Reagent Resource supported by HHSN272200900037C and OD10976. We thank the NIH AIDS Research and Reference Reagent Program for TZM-bl cells. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIH), Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIH), and, in part, with federal funds from the National Cancer Institute (NIH) under contract number HHSN261200800001E (J.D.L.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The research was also funded in part by the following grants: Collaboration for AIDS Vaccine Discovery grant OPP1033115 (M.C.N.); NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N.); Bill and Melinda Gates Foundation grants OPP1092074 and OPP1124068 (M.C.N.); NIH HIVRAD P01 AI100148 (M.C.N.); the Robertson Foundation to M.C.N. M.C.N. is a Howard Hughes Medical Institute Investigator.