ABSTRACT
Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 µg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.
Subject(s)
Anti-HIV Agents/administration & dosage , Antibodies, Neutralizing/immunology , HIV Antibodies/immunology , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/growth & development , HIV-1/immunology , Adolescent , Adult , Aged , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/therapeutic use , Binding Sites/drug effects , Binding Sites/immunology , Broadly Neutralizing Antibodies , CD4 Antigens/metabolism , Disease Reservoirs/virology , Drug Administration Schedule , Female , HIV Antibodies/administration & dosage , HIV Antibodies/therapeutic use , HIV Envelope Protein gp160/antagonists & inhibitors , HIV Envelope Protein gp160/chemistry , HIV Envelope Protein gp160/immunology , HIV Envelope Protein gp160/metabolism , HIV Infections/immunology , HIV-1/drug effects , Historically Controlled Study , Humans , Male , Middle Aged , Proviruses/drug effects , Proviruses/growth & development , Proviruses/immunology , Time Factors , Tissue Distribution , Viral Load/drug effects , Viral Load/immunology , Young AdultABSTRACT
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.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , HIV Antibodies/therapeutic use , HIV Infections/therapy , HIV-1/immunology , Immunization, Passive/methods , Viremia/therapy , Adult , Amino Acid Sequence , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/administration & dosage , Antibody Formation , Broadly Neutralizing Antibodies , Female , HIV Antibodies/administration & dosage , HIV Infections/immunology , HIV-1/classification , HIV-1/genetics , Humans , Immunity, Humoral , Male , Middle Aged , Phylogeny , Viremia/immunology , Young AdultABSTRACT
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.
