Dual-Affinity Re-Targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells

J Clin Invest. 2015 Nov 2;125(11):4077-90. doi: 10.1172/JCI82314. Epub 2015 Sep 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use
  • Antibodies, Bispecific / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology*
  • Genes, Reporter
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp41 / immunology*
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • Humans
  • Immunotherapy / methods*
  • Jurkat Cells
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes, Cytotoxic / immunology*
  • Virus Activation / immunology
  • Virus Latency

Substances

  • Anti-HIV Agents
  • Antibodies, Bispecific
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • gp120 protein, Human immunodeficiency virus 1
  • gp41 protein, Human immunodeficiency virus 1