HIV Infection Induces Extracellular Cathepsin B Uptake and Damage to Neurons

Sci Rep. 2019 May 29;9(1):8006. doi: 10.1038/s41598-019-44463-1.

Abstract

HIV-associated neurocognitive disorders prevail in 20-50 percent of infected individuals. Macrophages transmigrate through the blood brain barrier during HIV-1 infection, triggering neuronal dysfunction. HIV-infected macrophages secrete cathepsin B (CATB), and serum amyloid p component (SAPC), inducing neuronal apoptosis by an unknown mechanism. We hypothesized that HIV infection facilitates CATB/SAPC secretion from macrophages followed by neuronal internalization, promoting dysfunction. SK-N-SH neuronal cells were exposed to active recombinant histidine-tagged cathepsin B (His-CATB). His-CATB entry was tracked by intracellular flow cytometry, and neuronal dysfunction was verified by western blot. Macrophage-derived extracellular vesicles (EVs) were tested for the presence of CATB and SAPC. Neurons internalized His-CATB, an effect that was partially decreased by pre-treatment with anti-CATB antibody. Pre-treatment with CATB and SAPC antibodies decreased cleavage of caspase-3 and restored synaptophysin in neurons. Neurons exposed to macrophage-conditioned media differentially internalized His-CATB, dependent on the HIV replication levels. Finally, CATB and SAPC were secreted in EVs. We report for the first time that CATB is secreted from macrophages both free and in EVs, and is internalized by neurons. Moreover, HIV-replication levels modulate the amount of CATB neuronal uptake, and neuronal dysfunction can be decreased with CATB antibodies. In conclusion, the CATB/SAPC complex represents a novel target against HIV-associated neurocognitive disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / genetics*
  • AIDS Dementia Complex / metabolism
  • AIDS Dementia Complex / physiopathology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blood-Brain Barrier / metabolism
  • Caspase 3 / genetics
  • Cathepsin B / genetics*
  • Cathepsin B / metabolism
  • Cell Line
  • Cells, Cultured
  • Culture Media, Conditioned / metabolism
  • Culture Media, Conditioned / pharmacology
  • Deoxyribonucleases, Type II Site-Specific
  • Endoribonucleases / genetics*
  • Endoribonucleases / metabolism
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / pathology
  • Flow Cytometry
  • HIV Infections / complications
  • HIV Infections / metabolism*
  • HIV Infections / physiopathology
  • HIV-1 / pathogenicity
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Histidine / metabolism
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neurons / metabolism*
  • Neurons / pathology
  • Synaptophysin / genetics

Substances

  • Culture Media, Conditioned
  • Neoplasm Proteins
  • Synaptophysin
  • Histidine
  • Endoribonucleases
  • CCCGGG-specific type II deoxyribonucleases
  • Deoxyribonucleases, Type II Site-Specific
  • SAPC protein, human
  • Caspase 3
  • Cathepsin B