Combination therapy with anti-HIV-1 antibodies maintains viral suppression
Pilar Mendoza, Henning Gruell, Lilian Nogueira, Joy A Pai, Allison L Butler, Katrina Millard, Clara Lehmann, Isabelle Suárez, Thiago Y Oliveira, Julio C C Lorenzi, Yehuda Z Cohen, Christoph Wyen, Tim Kümmerle, Theodora Karagounis, Ching-Lan Lu, Lisa Handl, Cecilia Unson-O'Brien, Roshni Patel, Carola Ruping, Maike Schlotz, Maggi Witmer-Pack, Irina Shimeliovich, Gisela Kremer, Eleonore Thomas, Kelly E Seaton, Jill Horowitz, Anthony P West Jr, Pamela J Bjorkman, Georgia D Tomaras, Roy M Gulick, Nico Pfeifer, Gerd Fätkenheuer, Michael S Seaman, Florian Klein, Marina Caskey, Michel C Nussenzweig, Pilar Mendoza, Henning Gruell, Lilian Nogueira, Joy A Pai, Allison L Butler, Katrina Millard, Clara Lehmann, Isabelle Suárez, Thiago Y Oliveira, Julio C C Lorenzi, Yehuda Z Cohen, Christoph Wyen, Tim Kümmerle, Theodora Karagounis, Ching-Lan Lu, Lisa Handl, Cecilia Unson-O'Brien, Roshni Patel, Carola Ruping, Maike Schlotz, Maggi Witmer-Pack, Irina Shimeliovich, Gisela Kremer, Eleonore Thomas, Kelly E Seaton, Jill Horowitz, Anthony P West Jr, Pamela J Bjorkman, Georgia D Tomaras, Roy M Gulick, Nico Pfeifer, Gerd Fätkenheuer, Michael S Seaman, Florian Klein, Marina Caskey, Michel C Nussenzweig
Abstract
Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.
Figures
References
- Doitsh G & Greene WC Dissecting How CD4 T Cells Are Lost During HIV Infection. Cell Host Microbe 19, 280–291, doi:10.1016/j.chom.2016.02.012 (2016).
- Churchill MJ, Deeks SG, Margolis DM, Siliciano RF & Swanstrom R HIV reservoirs: what, where and how to target them. Nat Rev Microbiol 14, 55–60, doi:10.1038/nrmicro.2015.5 (2016).
- Nishimura Y et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563, doi:10.1038/nature21435 (2017).
- Gautam R et al. A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med, doi:10.1038/s41591-018-0001-2 (2018).
- Schoofs T et al. HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science 352, 997–1001, doi:10.1126/science.aaf0972 (2016).
- Caskey M et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491, doi:10.1038/nature14411 (2015).
- Lynch RM et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med 7, 319ra206, doi:10.1126/scitranslmed.aad5752 (2015).
- Caskey M et al. Antibody 10–1074 suppresses viremia in HIV-1-infected individuals. Nat Med 23, 185–191, doi:10.1038/nm.4268 (2017).
- Scheid JF et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535, 556–560, doi:10.1038/nature18929 (2016).
- Li JZ et al. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS 30, 343–353, doi:10.1097/QAD.0000000000000953 (2016).
- Bar KJ et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N Engl J Med 375, 2037–2050, doi:10.1056/NEJMoa1608243 (2016).
- Shingai M et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med 211, 2061–2074, doi:10.1084/jem.20132494 (2014).
- Gautam R et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109, doi:10.1038/nature17677 (2016).
- Klein F et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118–122, doi:10.1038/nature11604 (2012).
- Horwitz JA et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A 110, 16538–16543, doi:10.1073/pnas.1315295110 (2013).
- Shingai M et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503, 277–280, doi:10.1038/nature12746 (2013).
- Trkola A et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat Med 11, 615–622, doi:10.1038/nm1244 (2005).
- Mehandru S et al. Adjunctive passive immunotherapy in human immunodeficiency virus type 1-infected individuals treated with antiviral therapy during acute and early infection. J Virol 81, 11016–11031, doi:10.1128/JVI.01340-07 (2007).
- Sarzotti-Kelsoe M et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods 409, 131–146, doi:10.1016/j.jim.2013.11.022 (2014).
- Cohen YZL, Krassnig JCC, Barton L, Burke JP, Pai L, Lu J, Mendoza C-L, Oliveira P, Sleckman TY, Millard C, Butler K, Dizon A, Belblidia JP, Witmer-Pack S, Shimeliovich M, Gulick I, Seaman RM, Jankovic MS, Caskey MS, Nussenzweig M, M. C. Analysis of HIV-1 latent reservoir and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. bioRxiv, doi:10.1101/324509 (2018).
- Robertson DL, Sharp PM, McCutchan FE & Hahn BH Recombination in HIV-1. Nature 374, 124–126, doi:10.1038/374124b0 (1995).
- Rothenberger MK et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci U S A 112, E1126–1134, doi:10.1073/pnas.1414926112 (2015).
- Kearney MF et al. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog 10, e1004010, doi:10.1371/journal.ppat.1004010 (2014).
- Lorenzi JC et al. Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. Proc Natl Acad Sci U S A 113, E7908–E7916, doi:10.1073/pnas.1617789113 (2016).
- Wang Z et al. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc Natl Acad Sci U S A 115, E2575–E2584, doi:10.1073/pnas.1720665115 (2018).
- Hosmane NN et al. Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. J Exp Med 214, 959–972, doi:10.1084/jem.20170193 (2017).
- Crooks AM et al. Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies. J Infect Dis 212, 1361–1365, doi:10.1093/infdis/jiv218 (2015).
- Poignard P et al. Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438 (1999).
- Scheid JF et al. A method for identification of HIV gp140 binding memory B cells in human blood. J Immunol Methods 343, 65–67, doi:10.1016/j.jim.2008.11.012 (2009).
- Escolano A, Dosenovic P & Nussenzweig MC Progress toward active or passive HIV-1 vaccination. J Exp Med 214, 3–16, doi:10.1084/jem.20161765 (2017).
- Kwong PD & Mascola JR HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. Immunity 48, 855–871, doi:10.1016/j.immuni.2018.04.029 (2018).
- Lu CL et al. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352, 1001–1004, doi:10.1126/science.aaf1279 (2016).
- Walker BD & Yu XG Unravelling the mechanisms of durable control of HIV-1. Nat Rev Immunol 13, 487–498, doi:10.1038/nri3478 (2013).
- Colby DJ et al. Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection. Nat Med, doi:10.1038/s41591-018-0026-6 (2018).
- Saez-Cirion A et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 9, e1003211, doi:10.1371/journal.ppat.1003211 (2013).
- Sneller MC et al. A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection. Sci Transl Med 9, doi:10.1126/scitranslmed.aan8848 (2017).
- Fidler S et al. Virological Blips and Predictors of Post Treatment Viral Control After Stopping ART Started in Primary HIV Infection. J Acquir Immune Defic Syndr 74, 126–133, doi:10.1097/QAI.0000000000001220 (2017).
- Martin GE et al. Post-treatment control or treated controllers? Viral remission in treated and untreated primary HIV infection. AIDS 31, 477–484, doi:10.1097/QAD.0000000000001382 (2017).
- Cohn LB et al. Clonal CD4(+) T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat Med 24, 604–609, doi:10.1038/s41591-018-0017-7 (2018).
- Maldarelli F et al. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345, 179–183, doi:10.1126/science.1254194 (2014).
- Wagner TA et al. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345, 570–573, doi:10.1126/science.1256304 (2014).
- Cohn LB et al. HIV-1 integration landscape during latent and active infection. Cell 160, 420–432, doi:10.1016/j.cell.2015.01.020 (2015).
- Halper-Stromberg A et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158, 989–999, doi:10.1016/j.cell.2014.07.043 (2014).
- Ko SY et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 514, 642–645, doi:10.1038/nature13612 (2014).
- Gaudinski MR et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. PLoS Med 15, e1002493, doi:10.1371/journal.pmed.1002493 (2018).
- Salazar-Gonzalez JF et al. Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing. J Virol 82, 3952–3970, doi:10.1128/JVI.02660-07 (2008).
- Kirchherr JL et al. High throughput functional analysis of HIV-1 env genes without cloning. J Virol Methods 143, 104–111, doi:10.1016/j.jviromet.2007.02.015 (2007).
- Larkin MA et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948, doi:10.1093/bioinformatics/btm404 (2007).
- Guindon S et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 59, 307–321, doi:10.1093/sysbio/syq010 (2010).
- Stamatakis A RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30, 1312–1313, doi:10.1093/bioinformatics/btu033 (2014).
Source: PubMed