vasoactive-intestinal-peptide and AIDS-Dementia-Complex

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.

Topics: AIDS Dementia Complex; Amino Acid Sequence; Animals; Animals, Newborn; Behavior, Animal; Cell Death; Cells, Cultured; Cytokines; Cytopathogenic Effect, Viral; Disease Models, Animal; HIV Envelope Protein gp120; Mice; Molecular Sequence Data; Neurons; Peptide Fragments; Peptide T; Rats; Species Specificity; Vasoactive Intestinal Peptide

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS Dementia Complex; Amino Acid Sequence; Animals; Calcinosis; CD4 Antigens; CD4-Positive T-Lymphocytes; Cell Survival; Central Nervous System; Child; Child Behavior Disorders; Child, Preschool; Cognition Disorders; Eye Diseases; Female; Global Health; Hippocampus; HIV; HIV Antibodies; HIV Envelope Protein gp120; Humans; Infant; Infant, Newborn; Male; Mice; Molecular Sequence Data; Molecular Structure; Neurons; Peptide T; Peripheral Nervous System Diseases; Receptors, Virus; Severity of Illness Index; Spinal Cord Diseases; Tomography, X-Ray Computed; Vacuoles; Vasoactive Intestinal Peptide

HIV-1 is associated with a neuroAIDS syndrome that includes cognitive impairment. Several components of HIV-1 are capable of affecting cognition, but which of these is the major mediator is unknown. We injected into the lateral cerebral ventricle of mice HIV-1 pseudoviruses expressing the full viral genome with or without the viral coat glycoproteins, gp120/gp41. Only virus possessing gp120/gp41 induced defects in memory as assessed in an active avoidance T-maze footshock paradigm. By itself, gp120 also induced impairments that were reversed by hippocampal cholinergic stimulation. Paradoxically, low doses of gp120 could improve memory. Such low-dose, paradoxic improvement is a characteristic of substances that impair memory by overstimulating pathways that normally sustain memory. Consistent with this, a low, but not a high, dose of gp120 reversed memory impairment induced by overstimulation of the VIPergic system, a memory-sustaining pathway. Further characterization showed that two strains of gp120 (SF and MN) were equally effective at improving memory and that, unlike other actions of gp120, glycation was not required. We conclude that (1) the predominant cognitive-impairing component of HIV-1 is its viral coat glycoproteins, (2) gp120 impairs memory by overstimulating pathways that normally sustain memory, (3) the cognitive effect of gp120 is mediated by its protein core, and (4) gp120 likely impairs memory by affecting the cholinergic/VIPergic system.

Topics: AIDS Dementia Complex; Animals; Capsid Proteins; Hippocampus; HIV-1; Male; Mice; Receptors, Cholinergic; Vasoactive Intestinal Peptide