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.
Buzy
J
J
Peptide Design, Germantown, MD 20852.
Brenneman
D E
DE
Pert
C B
CB
Martin
A
A
Salazar
A
A
Ruff
M R
MR
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000134:cerebrospinal fluid*; D006679:HIV Seropositivity / Q000134:cerebrospinal fluid*; D015497:HIV-1; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D015717:Peptide T / Q000502:physiology*; D011446:Prospective Studies
D002556:Cerebrospinal Fluid Proteins; D015699:HIV Envelope Protein gp120; D015717:Peptide T