Hypersensitivity of HIV-1-infected cells to reactive sulfonamide metabolites correlated to expression of the HIV-1 viral protein Tat

Impairment of human immunodeficiency virus (HIV)-infected cells to deal with reactive drug metabolites may be a mechanism for the increased rate of adverse drug reactions seen in AIDS. 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 mu M SMX-HA, there was a significant concentration-dependent increase in cell death in transfected cell lines expressing Tat compared with 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 with controls (P < 0.05). Sensitivity to reactive drug metabolites in HIV-infected cells seems to be mediated by the viral protein Tat.