Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies

Nat Commun. 2021 Jul 21;12(1):4436. doi: 10.1038/s41467-021-24608-5.

Abstract

Latent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cytomegalovirus / drug effects*
  • Cytomegalovirus / immunology
  • Cytomegalovirus Infections / virology
  • Gene Expression / drug effects
  • Genes, Immediate-Early / genetics
  • Humans
  • Lipopolysaccharide Receptors / metabolism
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Monocytes / virology
  • Receptors, Chemokine / metabolism
  • Signal Transduction / drug effects
  • Single-Domain Antibodies / metabolism
  • Single-Domain Antibodies / pharmacology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Viral Proteins / metabolism
  • Virus Activation / drug effects
  • Virus Latency / drug effects*

Substances

  • CD14 protein, human
  • Lipopolysaccharide Receptors
  • Receptors, Chemokine
  • Single-Domain Antibodies
  • US28 receptor, Cytomegalovirus
  • Viral Proteins