title: Dual-Affinity Re-Targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells.
abstract: Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity-mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4+ T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV-specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8+ T cell clearance of CD4+ T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected-patient resting CD4+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals.
authors.forename: Julia A M
authors.initials: JA
authors.lastname: Sung
authors.forename: Joy
authors.initials: J
authors.lastname: Pickeral
authors.forename: Liqin
authors.initials: L
authors.lastname: Liu
authors.forename: Sherry A
authors.initials: SA
authors.lastname: Stanfield-Oakley
authors.forename: Chia-Ying Kao
authors.initials: CY
authors.lastname: Lam
authors.forename: Carolina
authors.initials: C
authors.lastname: Garrido
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.forename: Mattia
authors.initials: M
authors.lastname: Bonsignori
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yang
authors.forename: Robert
authors.initials: R
authors.lastname: Parks
authors.forename: Nancie
authors.initials: N
authors.lastname: Archin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Allard
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kirchherr
authors.forename: JoAnn D
authors.initials: JD
authors.lastname: Kuruc
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Gay
authors.forename: Myron S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: Kelly
authors.initials: K
authors.lastname: Soderberg
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.forename: Paul
authors.initials: P
authors.lastname: Moore
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Nordstrom
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D018033:Antibodies, Bispecific / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D017930:Genes, Reporter; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019169:Jurkat Cells; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014775:Virus Activation / Q000276:immunology; D017735:Virus Latency
chemical_list: D019380:Anti-HIV Agents; D018033:Antibodies, Bispecific; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1