HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1

Insights into antibody therapy for HIV-1 Despite the success of antiretroviral therapy, HIV-1-infected individuals still harbor latent virus. Thus, other therapeutic strategies are needed. A single injection of a broad and potent monoclonal antibody targeting the HIV-1 envelope protein reduced viral loads in HIV-1-infected individuals, albeit only transiently. Lu et al. now report that antibody treatment not only blocked free virus from infecting new cells, it also accelerated the clearance of infected cells. Furthermore, Schoofs et al. demonstrate that therapeutic antibody treatment enhanced infected individuals' humoral response against the virus. Thus, neutralizing antibodies may be a promising therapy for HIV-1 because of their potential to reduce the viral reservoir. Science, this issue pp. 1001 and 997 Clinical and animal data confirm that HIV-1 immunotherapy boosts infected cell clearance and immune responses against the virus. 3BNC117 is a broad and potent neutralizing antibody to HIV-1 that targets the CD4 binding site on the viral envelope spike. When administered passively, this antibody can prevent infection in animal models and suppress viremia in HIV-1–infected individuals. Here we report that HIV-1 immunotherapy with a single injection of 3BNC117 affects host antibody responses in viremic individuals. In comparison to untreated controls that showed little change in their neutralizing activity over a 6-month period, 3BNC117 infusion significantly improved neutralizing responses to heterologous tier 2 viruses in nearly all study participants. We conclude that 3BNC117-mediated immunotherapy enhances host humoral immunity to HIV-1.

[1]  T. Kepler,et al.  Two Distinct Broadly Neutralizing Antibody Specificities of Different Clonal Lineages in a Single HIV-1-Infected Donor: Implications for Vaccine Design , 2012, Journal of Virology.

[2]  Richard T. Wyatt,et al.  Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals , 2009, Nature.

[3]  Ron Diskin,et al.  HIV therapy by a combination of broadly neutralizing antibodies in humanized mice , 2012, Nature.

[4]  Chaim A. Schramm,et al.  Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies , 2014, Nature.

[5]  Philip R. Johnson,et al.  Passive Immunotherapy in Simian Immunodeficiency Virus-Infected Macaques Accelerates the Development of Neutralizing Antibodies , 2004, Journal of Virology.

[6]  J. Ravetch,et al.  The role of Fc–FcγR interactions in IgG-mediated microbial neutralization , 2015, The Journal of experimental medicine.

[7]  Christos J. Petropoulos,et al.  Neutralizing Antibody Responses against Autologous and Heterologous Viruses in Acute versus Chronic Human Immunodeficiency Virus (HIV) Infection: Evidence for a Constraint on the Ability of HIV To Completely Evade Neutralizing Antibody Responses , 2006, Journal of Virology.

[8]  Florian Klein,et al.  Computational analysis of anti–HIV-1 antibody neutralization panel data to identify potential functional epitope residues , 2013, Proceedings of the National Academy of Sciences.

[9]  A. Lapedes,et al.  Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants , 2015, Viruses.

[10]  Hanneke Schuitemaker,et al.  Isolation and propagation of HIV-1 on peripheral blood mononuclear cells , 2008, Nature Protocols.

[11]  M. Nussenzweig,et al.  A mouse model for HIV-1 entry , 2012, Proceedings of the National Academy of Sciences.

[12]  Florian Klein,et al.  Antibodies in HIV-1 Vaccine Development and Therapy , 2013, Science.

[13]  Ron Diskin,et al.  Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding , 2011, Science.

[14]  Feng Gao,et al.  Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies , 2014, Cell.

[15]  Peter B Gilbert,et al.  Two‐Sample Tests for Comparing Intra‐Individual Genetic Sequence Diversity between Populations , 2005, Biometrics.

[16]  Michael S. Seaman,et al.  Therapeutic Efficacy of Potent Neutralizing HIV-1-Specific Monoclonal Antibodies in SHIV-Infected Rhesus Monkeys , 2013, Nature.

[17]  O. Gascuel,et al.  New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. , 2010, Systematic biology.

[18]  Michael M. Desai,et al.  Global epistasis makes adaptation predictable despite sequence-level stochasticity , 2014, Science.

[19]  N. Haigwood,et al.  Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques , 2010, Nature Medicine.

[20]  A. Chakraborty,et al.  Enhanced clearance of HIV-1-infected cells by anti-HIV-1 broadly neutralizing antibodies in vivo , 2016 .

[21]  Xiping Wei,et al.  Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies , 2005, Journal of Virology.

[22]  Tongqing Zhou,et al.  Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 , 2010, Science.

[23]  Sergei L. Kosakovsky Pond,et al.  DIVEIN: a web server to analyze phylogenies, sequence divergence, diversity, and informative sites. , 2010, BioTechniques.

[24]  S. Ratcliffe,et al.  GEEQBOX: A MATLAB Toolbox for Generalized Estimating Equations and Quasi-Least Squares , 2008 .

[25]  Lynn Morris,et al.  Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein , 2012, The Journal of experimental medicine.

[26]  Florian Klein,et al.  Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy , 2014, Cell.

[27]  Mario Roederer,et al.  Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1 , 2010, Science.

[28]  L. Morris,et al.  Virological features associated with the development of broadly neutralizing antibodies to HIV-1. , 2015, Trends in microbiology.

[29]  Tongqing Zhou,et al.  Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization , 2013, Cell.

[30]  J. Ravetch,et al.  Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect , 2015, Cell.

[31]  M. Nussenzweig,et al.  Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia , 2013, Nature.

[32]  R. Ahmed,et al.  Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy , 2015, Cell.

[33]  J. Overbaugh,et al.  Early development of broad neutralizing antibodies in HIV-1 infected infants , 2014, Nature Medicine.

[34]  M. Altfeld,et al.  Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1 , 2011, PLoS pathogens.

[35]  Holly Janes,et al.  Tiered Categorization of a Diverse Panel of HIV-1 Env Pseudoviruses for Assessment of Neutralizing Antibodies , 2009, Journal of Virology.

[36]  Michael S. Seaman,et al.  Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117 , 2015, Nature.

[37]  A. Chakraborty,et al.  Enhanced clearance of HIV-1–infected cells by broadly neutralizing antibodies against HIV-1 in vivo , 2016, Science.

[38]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[39]  L. M. Mansky,et al.  Activity of a Novel Combined Antiretroviral Therapy of Gemcitabine and Decitabine in a Mouse Model for HIV-1 , 2012, Antimicrobial Agents and Chemotherapy.

[40]  Rolf Kaiser,et al.  HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice , 2013, Proceedings of the National Academy of Sciences.

[41]  B. Korber,et al.  Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection , 2014, AIDS.

[42]  Lynn Morris,et al.  Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies , 2015, Nature Medicine.

[43]  Martin A. Nowak,et al.  Antibody neutralization and escape by HIV-1 , 2003, Nature.

[44]  Ramón Doallo,et al.  CircadiOmics: integrating circadian genomics, transcriptomics, proteomics and metabolomics , 2012, Nature Methods.

[45]  Lynn Morris,et al.  Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape , 2012, Nature Medicine.

[46]  J. Ravetch,et al.  Fcγ receptor pathways during active and passive immunization , 2015, Immunological reviews.

[47]  H. Liao,et al.  High throughput functional analysis of HIV-1 env genes without cloning. , 2007, Journal of virological methods.

[48]  Raphael Gottardo,et al.  Global Panel of HIV-1 Env Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies , 2013, Journal of Virology.

[49]  Chaim A. Schramm,et al.  Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus , 2013, Nature.

[50]  Shane S. Sturrock,et al.  Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data , 2012, Bioinform..

[51]  David C. Nickle,et al.  HIV-Specific Probabilistic Models of Protein Evolution , 2007, PloS one.

[52]  E E Giorgi,et al.  A note on two-sample tests for comparing intra-individual genetic sequence diversity between populations. , 2012, Biometrics.

[53]  Pham Phung,et al.  Broad neutralization coverage of HIV by multiple highly potent antibodies , 2011, Nature.