Received for publication March 4, 2005.
Revised May 26, 2005.
Accepted for publication May 27, 2005.

Hypersensitivity of HIV-1 Infected Cells to Reactive Sulfonamide Metabolites Correlated to Expression of the HIV-1 Viral Protein Tat

Abstract

Impairment of HIV-infected cells to deal with reactive drug metabolites may be a mechanism for the increased rate of adverse drug reactions seen in AIDS. Human Immunodeficiency Virus (HIV) Tat protein expression may be associated with increased oxidative stress within HIV-infected cells. To determine the relationship between expression of HIV Tat and sensitivity to reactive drug metabolites, we studied toxicity of sulfamethoxazole (SMX) and its reactive hydroxylamine intermediate (SMX-HA) in lymphocytes transfected with the HIV tat gene. Over a concentration range from 0 to 400 µM SMX-HA, there was a significant concentration-dependent increase in cell death in transfected cell lines expressing Tat compared to controls. Jurkat T cells transfected with a dose dependent inducible tat gene showed increased toxicity in response to SMX-HA as more Tat expression was induced. Enhanced sensitivity to SMX-HA was accompanied by significantly lower concentrations of total intracellular glutathione compared to controls (P<0.05). Sensitivity to reactive drug metabolites in HIV infected cells appears to be mediated by the viral protein Tat.

Key words: HIV, adverse drug reactions, reactive metabolites, sulfonamides, tat, toxicity

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