Impairment of excitatory amino acid transport in astroglial cells infected with the human immunodeficiency virus type 1.
Perturbation of astrocyte functions by HIV-1 infection may contribute to the pathogenesis of AIDS dementia complex (ADC). The present study investigated the possibility that astroglial transport of glutamate and aspartate, the major excitatory amino acids (EAAs) in the mammalian central nervous system (CNS), is altered by HIV-1 infection. Human U251 glioma cells were infected with the brain isolate SF162 of HIV-1. HIV-1 persisted in glial cells over several months. This nonproductive infection of glial cells was characterized by persistent expression of Nef over the time of the infection, and the transient presence of structural viral proteins, including the viral transmembrane glycoprotein gp41, which was detected during the initial 2 weeks following HIV-1 infection. The presence of gp41 in acutely HIV-1-infected glial cells coincided with a 36% decrease in D-[3H]aspartate uptake, owing to a reduction in the maximal transport capacity (vmax) for D-aspartate. The expression of typical astrocytic glutamate transporters EAAT1 and EAAT2 in U251 glioma cells was not altered by HIV-1 infection. To determine whether viral protein gp120, gp41, or Nef was involved in the impairment of EAA transport in acutely HIV-1-infected glial cells, effects of lentiviral lytic peptide type 1 (LLP-1) (corresponding to the carboxy terminus of gp41), recombinant SF2 gp120, and recombinant LAI Nef on D-[3H]aspartate uptake and the release of glutamate in glial cells were investigated. Only LLP-1 reduced D-[3H]aspartate uptake and facilitated the release of glutamate from glial cells in a concentration-dependent manner. These results suggest that the carboxy terminus of gp41 impairs EAA transport in glial cells, which may contribute to excitotoxic damage to neurons in HIV-1 infection of the CNS.
Kort
J J
JJ
Department of Medicine, Albany Medical College, New York 12208, USA.
D001224:Aspartic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D001692:Biological Transport / Q000187:drug effects; D015693:Gene Products, nef / Q000378:metabolism; D005910:Glioma; D018698:Glutamic Acid / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D014407:Tumor Cells, Cultured; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C116049:lentiviral lytic peptide type 1, Human immunodeficiency virus 1; D054311:nef Gene Products, Human Immunodeficiency Virus; D001224:Aspartic Acid; D018698:Glutamic Acid