A potent anti-HIV immunotoxin blocks spreading infection by primary HIV type 1 isolates in multiple cell types

AIDS Res Hum Retroviruses. 2004 Feb;20(2):145-50. doi: 10.1089/088922204773004851.

Abstract

Although several immunotoxins that selectively kill HIV-1-infected cells have been described, their clinical utility is limited by low potency against spreading viral infection. We show here that changing the carboxyterminal sequence of an anti-HIV-1 envelope immunotoxin to the consensus endoplasmic reticulum retention sequence KDEL substantially improves its ability to block infection of peripheral blood mononuclear cells by primary HIV-1 isolates without increasing nonspecific toxicity. Polychromatic flow cytometry of peripheral blood mononuclear cells (PBMC) infected with an HIV-1-GFP reporter virus demonstrated that the improved immunotoxin is active against a variety of primary cell types including memory T cells, NK-T cells, and monocyte/macrophages. The subnanomolar potency of this agent suggests that it could be clinically useful either as an adjuvant to highly active antiretroviral therapy (HAART) in drug-resistant patients or to reduce the reservoir of latently infected cells that is implicated in HIV-1 persistence.

MeSH terms

  • ADP Ribose Transferases / genetics
  • ADP Ribose Transferases / pharmacology
  • Animals
  • Antiretroviral Therapy, Highly Active
  • Bacterial Toxins / genetics
  • Bacterial Toxins / pharmacology
  • CHO Cells
  • Cells, Cultured
  • Chemotherapy, Adjuvant
  • Cricetinae
  • Exotoxins / genetics
  • Exotoxins / pharmacology
  • Genes, Reporter
  • Green Fluorescent Proteins
  • HIV Antibodies / genetics
  • HIV Antibodies / pharmacology
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / pathogenicity*
  • Humans
  • Immunotoxins / genetics
  • Immunotoxins / pharmacology*
  • In Vitro Techniques
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Luminescent Proteins / genetics
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / virology
  • Oligopeptides
  • Protein Sorting Signals
  • Pseudomonas aeruginosa Exotoxin A
  • Virulence Factors / genetics
  • Virulence Factors / pharmacology

Substances

  • Bacterial Toxins
  • Exotoxins
  • HIV Antibodies
  • Immunotoxins
  • Luminescent Proteins
  • Oligopeptides
  • Protein Sorting Signals
  • Virulence Factors
  • lysyl-aspartyl-glutamyl-leucine
  • Green Fluorescent Proteins
  • ADP Ribose Transferases