title: Targeting HIV Reservoir in Infected CD4 T Cells by Dual-Affinity Re-targeting Molecules (DARTs) that Bind HIV Envelope and Recruit Cytotoxic T Cells.
abstract: HIV reservoirs and production of viral antigens are not eliminated in chronically infected participants treated with combination antiretroviral therapy (cART). Novel therapeutic strategies aiming at viral reservoir elimination are needed to address chronic immune dysfunction and non-AIDS morbidities that exist despite effective cART. The HIV envelope protein (Env) is emerging as a highly specific viral target for therapeutic elimination of the persistent HIV-infected reservoirs via antibody-mediated cell killing. Dual-Affinity Re-Targeting (DART) molecules exhibit a distinct mechanism of action via binding the cell surface target antigen and simultaneously engaging CD3 on cytotoxic T lymphocytes (CTLs). We designed and evaluated Env-specific DARTs (HIVxCD3 DARTs) derived from known antibodies recognizing diverse Env epitopes with or without broadly neutralizing activity. HIVxCD3 DARTs derived from PGT121, PGT145, A32, and 7B2, but not VRC01 or 10E8 antibodies, mediated potent CTL-dependent killing of quiescent primary CD4 T cells infected with diverse HIV isolates. Similar killing activity was also observed with DARTs structurally modified for in vivo half-life extension. In an ex vivo model using cells isolated from HIV-infected participants on cART, combinations of the most potent HIVxCD3 DARTs reduced HIV expression both in quiescent and activated peripheral blood mononuclear cell cultures isolated from HIV-infected participants on suppressive cART. Importantly, HIVxCD3 DARTs did not induce cell-to-cell virus spread in resting or activated CD4 T cell cultures. Collectively, these results provide support for further development of HIVxCD3 DARTs as a promising therapeutic strategy for targeting HIV reservoirs.
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Sloan
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, United States of America.
authors.forename: Chia-Ying Kao
authors.initials: CY
authors.lastname: Lam
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Alivelu
authors.initials: A
authors.lastname: Irrinki
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, United States of America.
authors.forename: Liqin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Tsai
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Pace
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Murry
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Mini
authors.initials: M
authors.lastname: Balakrishnan
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, United States of America.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moore
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, United States of America.
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Nordstrom
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.affiliation: MacroGenics, Inc., Rockville, Maryland, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
mesh_terms: D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D015483:HIV Antibodies / Q000276:immunology / Q000627:therapeutic use; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology*
chemical_list: D015704:CD4 Antigens; D015483:HIV Antibodies