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

Satoshi Kubota, Shubhra Shetty, Huizhong Zhang, Shigehisa Kitahara, Roger J. Pomerantz

Research output: Contribution to journalArticle

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Abstract

The anti-human immunodeficiency virus type I (anti-HIV-l) effects of γ- glutamylcysteine ethyl ester (γ-GCE; TEI-2306) were examined in vitro. In initial studies using a vigorously HIV-1-producing human T-lymphocytic cell line, γ-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, γ-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 γ-GCE concentrations. At lower concentrations (200 to 400 μM), γ-GCE significantly repressed the virus production from chronically HIV-l-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 γ-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, γ-GCE at such concentrations was found to directly inhibit the infectivity of HIV-1 within 4 h. Repressive effects of γ-GCE on acute HIV-1 infection in human primary human peripheral blood mononuclear cells were also demonstrated. Here, the anti-HIV-1 strategy utilizing γ-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-l-infected individuals.

Original languageEnglish
Pages (from-to)1200-1206
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume42
Issue number5
Publication statusPublished - May 1998
Externally publishedYes

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HIV-1
Esters
HIV
HIV Infections
Glutathione
Poisons
Prodrugs
Blood Cells
Cell Survival
Cell Death
Antioxidants
Viruses
Cell Line
Growth

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Novel inhibitory effects of γ-glutamylcysteine ethyl ester against human immunodeficiency virus type 1 production and propagation. / Kubota, Satoshi; Shetty, Shubhra; Zhang, Huizhong; Kitahara, Shigehisa; Pomerantz, Roger J.

In: Antimicrobial Agents and Chemotherapy, Vol. 42, No. 5, 05.1998, p. 1200-1206.

Research output: Contribution to journalArticle

Kubota, Satoshi ; Shetty, Shubhra ; Zhang, Huizhong ; Kitahara, Shigehisa ; Pomerantz, Roger J. / Novel inhibitory effects of γ-glutamylcysteine ethyl ester against human immunodeficiency virus type 1 production and propagation. In: Antimicrobial Agents and Chemotherapy. 1998 ; Vol. 42, No. 5. pp. 1200-1206.
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