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Early antibody therapy can induce long-lasting immunity to SHIV

Abstract

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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Figure 1: Control of SHIVAD8-EO replication by a 2-week course of combination bNAb therapy.
Figure 2: Establishment of controller status in bNAb-treated animals inoculated with SHIVAD8-EO by the intrarectal route.
Figure 3: Establishment of controller status in bNAb-treated animals inoculated with SHIVAD8-EO by the intravenous route.
Figure 4: Depletion of CD8+ T cells in controller macaques results in the rapid induction of plasma viraemia.

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Acknowledgements

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.

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Authors and Affiliations

Authors

Contributions

Y.N., M.C.N., and M.A.M. designed experiments; Y.N., R.G., T.-W.C., R.S., K.E.F., M.S., F.K., A.G., J.G., O.K.D., R.J.P., and M.S.S. performed experiments; Y.N., T.-W.C., A.B.-W., M.S.S., J.D.L., R.A.K., A.S.F., M.C.N., and M.A.M. analysed data; Y.N., J.D.L., R.A.K., A.S.F., M.C.N., and M.A.M. wrote the manuscript.

Corresponding authors

Correspondence to Michel C. Nussenzweig or Malcolm A. Martin.

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The authors declare no competing financial interests.

Additional information

Reviewer Information Nature thanks R. Siliciano and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Sustained suppression of virus replication by a 2-week course of combination bNAb treatment after intrarectal SHIVAD8-EO challenge.

Plasma viral RNA levels and 10-1074 or 3BNC117 mAb concentrations after bNAb therapy beginning on day 3 after intrarectal challenge are shown (n = 6).

Extended Data Figure 2 Sustained suppression of virus replication by a 2-week course of combination bNAb treatment after intravenous SHIVAD8-EO challenge.

Plasma viral RNA levels and 10-1074 or 3BNC117 mAb concentrations after bNAb therapy beginning on day 3 after intravenous challenge are shown (n = 7).

Extended Data Figure 3 Analyses of selected SHIVAD8 gp120 sequences known to confer resistance to 10-1074 or 3BNC117 mAbs present in virus rebounding after immunotherapy.

Nucleotide sequences present in amplicons, obtained from animals DELV (day 84 after infection), DEWL (day 72 after infection), DF06 (day 99 after infection), or MAF (day 90 after infection) during virus rebound (shown in Extended Data Fig. 2d–g), were evaluated. SHIVAD8-EO gp120 sequences are shown at the top. Mutations conferring resistance to 10-1074 (vertical bars) and 3BNC117 (horizontal bars) are highlighted.

Extended Data Figure 4 CD8+ T-cell responses and memory phenotype.

a, Memory CD8+ T-cell responses to SIVmac239 Gag measured by intracellular cytokine staining as a sum of IFN-γ, IL-2, TNF, CD107a, MIP-1B, and IL-10. Supp, during bNAb-mediated viral suppression; Peak, during peak of virus rebound; Base, after resolution of rebound; Late, during late stage of virus infection; coloured bars, mean; whiskers, s.e.m. b, Polyfunctionality of the CD8+ T-cell responses in macaques inoculated by the intravenous route. c, CD8+ T-cell memory subsets in macaques inoculated by the intravenous route. N, naive; CM, central memory; EM, effector memory; TEM, terminal effector memory.

Extended Data Figure 5 FACS analyses of CD8+ cells in controller animals after administration of depleting anti-CD8 mAbs.

CD8+ lymphocytes were collected from controller monkeys MVJ, DEWL, and DEMR after infusion of the MT807R1anti-CD8α mAb (a, b) or the CD8b255R1 anti-CD8β mAb (c, d) and the CD3+CD8+ and CD3CD8+ fractions determined.

Extended Data Figure 6 Administration of cART during the acute SHIVAD8-EO infection of macaques does not result in controller status.

cART (tenofovir, emtricitabine, and raltagravir) was administered daily to three animals for 15 weeks beginning on day 3 after intrarectal challenge with 1,000 TCID50 of SHIVAD8-EO.

Extended Data Table 1 Plasma viral RNA levels in macaques by ultrasensitive RT–PCR assay
Extended Data Table 2 Circulating CD4+ T-cell frequency in controller monkeys capable of releasing replication-competent SHIVAD8-EO by virus outgrowth assay

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Nishimura, Y., Gautam, R., Chun, TW. et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563 (2017). https://doi.org/10.1038/nature21435

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