Novel inhibitory effects of gamma-glutamylcysteine ethyl ester against human immunodeficiency virus type 1 production and propagation.

Abstract

The anti-human immunodeficiency virus type I (anti-HIV-1) effects of gamma-glutamylcysteine ethyl ester (gamma-GCE; TEI-2306) were examined in vitro. In initial studies using a vigorously HIV-1-producing human T-lymphocytic cell line, gamma-GCE displayed a novel biphasic repressive effect on chronic HIV-1 infection that was unlike that of other glutathione prodrugs or other reported antioxidants. In high doses, up to a concentration of 2.5 mM, at which neither glutathione (GSH) nor another GSH precursor has shown inhibitory effects, gamma-GCE potently inhibited the production of HIV-1 by a selective cytopathic effect against infected cells, while the viability and growth of uninfected cells were unaffected at the same gamma-GCE concentrations. At lower concentrations (200 to 400 microM), gamma-GCE significantly repressed the virus production from chronically HIV-1-expressing cells without affecting their viability. The discrepancy of the thresholds of the toxic doses between infected and uninfected cells was found to be more than 10-fold. Relatively high doses of gamma-GCE, utilized in acute HIV-1 infection of T-lymphocytic cells, entirely blocked the propagation of HIV-1 and rescued the cells from HIV-1-induced cell death. Furthermore, gamma-GCE at such concentrations was found to directly inhibit the infectivity of HIV-1 within 4 h. Repressive effects of gamma-GCE on acute HIV-1 infection in human primary human peripheral blood mononuclear cells were also demonstrated. Here, the anti-HIV-1 strategy utilizing gamma-GCE is removal of both HIV-1-producing cells and free infectious HIV-1 in vitro, in place of specific immunoclearance in vivo, which might lead to an arrest or slowing of viral propagation in HIV-1-infected individuals.

• Authors: S Kubota, S Shetty, H Zhang, S Kitahara, R J Pomerantz
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 42 Issue 5 Pg. 1200-6 (May 1998) ISSN: 0066-4804 [Print] United States
• PMID: 9593150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antigens, Viral
• Dipeptides
• N-gamma-glutamylcysteine ethyl ester

Topics

• Anti-HIV Agents (chemistry, pharmacology)
• Antigens, Viral (analysis)
• Cell Count (drug effects)
• Dipeptides (chemistry, pharmacology)
• HIV-1 (drug effects, growth & development)
• Humans
• T-Lymphocytes (drug effects, virology)
• Virus Replication (drug effects)