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TOXICOLOGY

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

The BioTherapeutics Group, Robarts Research Institute London, Ontario, Canada (J.A., M.J.R., G.A.D.); Section of Paediatric Clinical Pharmacology, Departments of Paediatrics (M.J.T.), Physiology and Pharmacology (A.K., B.U.), and Medicine (D.F.), Children's Hospital of Western Ontario, University of Western Ontario, London, Ontario, Canada; and Departments of Medicine and Pharmacology, State University of New York, Health Sciences Center Syracuse, Syracuse, New York (D.L.)

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 µM 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.

Address correspondence to: Dr. M. Rieder, Department of Paediatrics, Children's Hospital of Western Ontario, 800 Commissioner's Rd. East, London, ON, Canada N6C 2V5. E-mail: mrieder{at}uwo.ca

This article has been cited by other articles:

				D. Lin, M J. Tucker, and M. J Rieder Increased Adverse Drug Reactions to Antimicrobials and Anticonvulsants in Patients with HIV Infection Ann. Pharmacother., September 1, 2006; 40(9): 1594 - 1601. [Abstract] [Full Text] [PDF]