Bispecific antibodies promote natural killer cell-mediated elimination of HIV-1 reservoir cells

Nat Immunol. 2024 Mar;25(3):462-470. doi: 10.1038/s41590-023-01741-5. Epub 2024 Jan 26.

Abstract

The persistence of CD4+ T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4+ T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir.

MeSH terms

  • Animals
  • Antibodies, Bispecific*
  • Cell Death
  • Cytotoxicity, Immunologic
  • HIV-1*
  • Humans
  • Killer Cells, Natural
  • Mice
  • Mice, Transgenic

Substances

  • Antibodies, Bispecific