title: Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.
abstract: Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Halper-Stromberg
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ching-Lan
authors.initials: CL
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Horwitz
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Bournazos
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Nogueira
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Eisenreich
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Cassie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schaefer
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Furze
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK.
authors.forename: Rab
authors.initials: R
authors.lastname: Prinjha
authors.affiliation: Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute. Electronic address: nussen@rockefeller.edu.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000008:administration & dosage; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D051379:Mice; D011961:Receptors, Fc / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D060908:CTLA-4 Antigen; C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D006877:Hydroxamic Acids; D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc; D000077337:Vorinostat