HIV-related neurotoxicity.
The central nervous system manifestations of AIDS were originally thought to consist solely of white matter lesions, but recent evidence has shown that a substantial degree of neuronal loss can also occur. This review presents evidence for HIV-related toxic factors that may account at least in part for this newly-recognized neuronal injury. One potential neurotoxin is the HIV-1 envelope glycoprotein gp-120 or a fragment of this molecule. This coat protein is shed by the virus and potentially released from HIV-infected immune cells. In tissue culture experiments on rodent neurons, gp120 produces an early rise in intracellular calcium concentration and, subsequently, delayed-onset neurotoxicity. In addition, HIV-infected macrophages or microglia release as yet undefined toxic factor(s) that kill rodent, chick, and human neurons in vitro. It is as yet unknown if one of these macrophage toxic factors might represent a gp120 fragment, or alternatively, if gp120, in the absence of HIV-1 infection, might be capable of activating macrophages to release these toxic factor(s). In at least some neuronal cell types, gp120-induced neurotoxicity can be prevented by antagonists of L-type voltage-dependent calcium channels or by antagonists of N-methyl-D-aspartate (NMDA, a subtype of glutamate receptor). Degradation of endogenous glutamate also protects neurons from gp120-related neuronal injury, suggesting that gp120 and glutamate are both necessary for neuronal cell death as synergistic effectors. Antagonists acting at the other types of glutamate receptors (non-NMDA antagonists) are ineffective in affording protection from gp120.(ABSTRACT TRUNCATED AT 250 WORDS)
Lipton
S A
SA
Department of Neurology, Children's Hospital, Beth Israel Hospital, Brigham.
D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D017628:Microglia / Q000473:pathology; D008954:Models, Biological; D009474:Neurons / Q000382:microbiology / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D015699:HIV Envelope Protein gp120; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium