gp120 as an etiologic agent for NeuroAIDS: neurotoxicity and model systems.
The search for an agent that can mediate the symptoms of NeuroAIDS has been directed at gp120, the major envelope protein from HIV. The toxicity associated with gp120 was examined as a model and predictor of the neuropathological and neuropsychiatric manifestations of AIDS. Studies of the neurotoxic effects of purified gp120 on neurons from the rodent CNS cell cultures indicated the following: potent and selective killing of subpopulations of hippocampal neurons; varying potency of gp120s obtained from various HIV isolates; complete and potent protection from gp120 killing action after treatment with peptides related to vasoactive intestinal peptide; and obligatory presence of glia for gp120-related toxicity. Investigations of gp120 treatment of rodents revealed: cortical neurodystrophy with reduced arborizations and swollen processes; delays in developmental behaviors involving motor skills; peptide T prevention or attenuation of the morphological and behavioral deficits/delays produced by administration of gp120; and impairment of learning in the Morris swim maze. In addition, studies of subcutaneously administered, radiolabeled gp120 in neonatal animals demonstrated the presence of toxic fragments of gp120 in the developing brain. With the use of model test systems of non-human derived cell cultures and neonatal rats, we have captured and predicted a number of the morphological and behavioral deficits associated with AIDS. These multi-disciplinary studies of the actions of gp120 and associated fragments in rodents and rodent cells predict that the loss of cognitive and neurological function in patients with AIDS are attributed in part to interference of critical brain functions by the envelope protein, gp120.
Brenneman
D E
DE
Section on Developmental and Molecular Pharmacology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
McCune
S K
SK
Mervis
R F
RF
Hill
J M
JM
D015526:AIDS Dementia Complex / Q000209:etiology* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D016923:Cell Death; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D015699:HIV Envelope Protein gp120 / Q000502:physiology* / Q000633:toxicity; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity; D015717:Peptide T / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D016207:Cytokines; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D015717:Peptide T; D014660:Vasoactive Intestinal Peptide