Potent gp120-like neurotoxic activity in the cerebrospinal fluid of HIV-infected individuals is blocked by peptide T.

The envelope protein of the human immunodeficiency virus (gp120) causes neuronal death in developing murine hippocampal cultures or rat retinal ganglion cells. In HIV-infected individuals, gp120 released from HIV-infected macrophages or other cells in the brain has been proposed as the etiology for the pathophysiology of AIDS central nervous system (CNS) disease by diffusing to act at a distance to cause damage and/or death to neighboring neurons. In this study, 28 cerebrospinal fluid (CSF) samples from HIV-infected individuals (79% were WR stage 1 and 2) and neurological disease controls were tested, blind to the investigator, for the presence of in vitro neuronal killing activity. Neurotoxic activity was detected with peak effects at a 1:10(5) dilution in CSF from 9/18 HIV-infected individuals and 1/10 neurological disease controls. Thus half of CSF from early stages of HIV disease are characterized by the presence of neurotoxic activity which is not present in control CSF (Fischers exact test, P < 0.05). The neuronal toxicity by patient CSF could be prevented by peptide T (1 nM). A monoclonal antibody to mouse CD4, RL.172, also attenuated or prevented CSF-induced neuronal killing in all four CSF samples tested. In addition, an antiserum to peptide T previously shown to bind gp120 and neutralize both infectively and direct gp120 neurotoxicity, neutralized the CSF factor. gp120, or a modified small fragment, is suggested to be the responsible toxic molecular entity. These results may be relevant to the pathophysiology of HIV-related CNS disease and the mechanism by which peptide T causes improvements.     

A VIP antagonist distinguishes VIP receptors on spinal cord cells and lymphocytes

Vasoactive intestinal peptide (VIP) is a neuropeptide which also interacts with cells of the immune system. The paucity of specific VIP receptor antagonists has hampered studies of possible receptor heterogeneity and of VIP function. To aid in achieving these goals, a new VIP antagonist, a hybrid between neurotensin and VIP, has been synthesized. This peptide interacted with VIP receptors on spinal cord cells with an affinity 10-fold greater than VIP itself. In contrast, 1000-fold higher concentrations of the antagonist were required to displace labeled VIP from its receptor on lymphoid cells as compared to VIP itself, suggesting VIP receptor heterogeneity between immune and spinal cord cells.     

Learning and sexual deficiencies in transgenic mice carrying a chimeric vasoactive intestinal peptide gene

The molecular mechanisms responsible for behavior are largely unknown. A state of the art model, paving the path from genes to behavior, is offered by transgenic animals. Candidate molecules are classic neuropeptides, such as vasoactive intestinal peptide (VIP). Transgenic mice harboring a chimeric VIP gene driven by the polyoma promoter were produced. Behavioral studies revealed learning impairment and prolonged retardation in memory acquisition in the genetically altered animals. Furthermore, reduced performance was observed when the male transgenic mice were tested for sexual activity in the presence of receptive females. Surprisingly, radioimmunoassays showed an approx 20% decrease in the VIP content of the transgenic mice brains. To directly assess genetically reduced VIP content as a cause for learning impairment, transgenic mice carrying diphtheria toxia-encoding sequences driven by the rat VIP promoter were created. These animals had reduced brain VIP and exhibited deficiencies in learning abilities, strongly supporting an important neurobiological function for VIP in vivo.