Journal Article

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Burke, Leah, Bar-On, Yotam, Nogueira, Lilian, Witmer-Pack, Maggi, Scheid, Johannes F., Braunschweig, Malte, Cohen, Yehuda Z., Walker, Bruce D., Caskey, Marina, Shimeliovich, Irina, Hadrigan, Sonya, Hawthorne, Thomas, Keler, Tibor, Bjorkman, Pamela J., Horwitz, Joshua A., Klein, Florian, Nussenzweig, Michel C., Pfeifer, Nico, Feldmann, Anna, Settler, Allison, Hahn, Beatrice H., Gulick, Roy M., Seaman, Michael S., Kreider, Edward F., Juelg, Boris, Zingman, Barry, Oliveira, Thiago, Lu, Ching-Lan, Learn, Gerald H., Lorenzi, Julio C. C., Schlesinger, Sarah J., Patel, Roshni, West, Jr, Anthony P.

2016

Overview

A phase IIa clinical trial shows that the administration of the broadly neutralizing antibody 3BNC117 delays viral rebound following the discontinuation of antiretroviral therapy in patients who were chronically infected with HIV-1. Super anti-HIV antibody tested A phase IIa clinical trial shows that the administration of the broadly neutralizing antibody 3BNC117, which targets the CD4 binding site of the HIV-1 Env protein, delays viral rebound following the discontinuation of antiretroviral therapy in patients who were chronically infected with HIV-1. The authors conclude that 3BNC117 effectively blocks emergence of antibody-sensitive viruses from HIV-1 reservoirs during analytical treatment interruption, a finding that could have significant implications for HIV-1 treatment initiatives. Interruption of combination antiretroviral therapy (ART) 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 (bNAb) against the CD4 binding site of HIV-1 Env 1 , in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, 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 administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/254 / 692/308/575 / Adolescent / Adult / Aged / Anti-HIV Agents - administration & dosage / Anti-HIV Agents - pharmacology / Anti-HIV Agents - therapeutic use / Antibodies, Monoclonal, Humanized / Antibodies, Neutralizing - administration & dosage / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - therapeutic use / Antiretroviral agents / Antiretroviral drugs / Antiviral agents / Binding sites / Binding Sites - drug effects / Binding Sites - immunology / Broadly Neutralizing Antibodies / CD4 Antigens - metabolism / Clinical trials / Disease Reservoirs - virology / Dosage and administration / Drug Administration Schedule / Drug therapy / Drug therapy, Combination / Female / Health aspects / Historically Controlled Study / HIV / HIV antibodies / HIV Antibodies - administration & dosage / HIV Antibodies - immunology / 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 infection / HIV Infections - drug therapy / HIV Infections - immunology / HIV Infections - virology / HIV-1 - drug effects / HIV-1 - growth & development / HIV-1 - immunology / Host-virus relationships / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immunoglobulins / letter / Male / Methods / Middle Aged / multidisciplinary / Prevention / Proviruses - drug effects / Proviruses - growth & development / Proviruses - immunology / Science / Time Factors / Tissue Distribution / Viral Load - drug effects / Viral Load - immunology / Young Adult