title: Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells.
abstract: To elucidate the pathogenic mechanisms involved in neurodegeneration in AIDS patients with cognitive deficits, we have examined the toxic effect of the lentivirus lytic peptide 1 (LLP-1) corresponding to the carboxyl terminus of HIV-1 transmembrane glycoprotein gp41 on human neuronal and glial cell lines. LLP-1 induced a significant lactate dehydrogenase (LDH, a marker of cell death) release from these cells in a concentration- and time-dependent manner, while the noncytolytic LLP-1 analog 2 had little effect. Application of LLP-1 to SH-SY5Y, a well-characterized human neuronal cell line, caused the decline of intracellular glutathione (GSH) content that appeared to occur before a significant LDH release. Furthermore, LLP-1 elicited a significant loss of mitochondrial function as measured by mitochondrial transmembrane potential (MTP). Among the reducing agents and antioxidants tested, GSH and a GSH prodrug N-acetylcysteine (NAC) provided protection against LLP-1-induced neuronal cell death, evidently by restoring the intracellular GSH levels and blocking the disruption of mitochondrial integrity. Thus, gp41-derived LLP-1 may be a potential neurotoxic agent capable of causing the intracellular GSH depletion and disturbing the mitochondrial function, possibly contributing to the neurodegenerative cascade as seen in HIV-1-associated dementia. Our data indicate that restoring both GSH concentration and mitochondrial function may hold promise as possible therapeutic strategies for slowing disease progression of dementia in AIDS patients.
authors.affiliation: Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Medical Research Center, Ewha Womans University, Yangcheonku, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Sung
authors.forename: S A
authors.initials: SA
authors.lastname: Shin
authors.forename: H K
authors.initials: HK
authors.lastname: Park
authors.forename: R C
authors.initials: RC
authors.lastname: Montelaro
authors.forename: Y H
authors.initials: YH
authors.lastname: Chong
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy; D000111:Acetylcysteine / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000032:analysis / Q000494:pharmacology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000633:toxicity*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D011355:Prodrugs / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D015700:HIV Envelope Protein gp41; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011355:Prodrugs; C116049:lentiviral lytic peptide type 1, Human immunodeficiency virus 1; D005978:Glutathione; D000111:Acetylcysteine