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Antimicrobial Agents and Chemotherapy, September 2002, p. 2865-2871, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2865-2871.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Immunomodulatory Effect of Zidovudine (ZDV) on Cytotoxic T Lymphocytes Previously Exposed to ZDV

Sabine Francke,^1, Charles G. Orosz,^2,3,4 Jason Hsu,³ and Lawrence E. Mathes^1,3,4*

Department of Veterinary Biosciences, College of Veterinary Medicine,¹ Department of Surgery, College of Medicine,² ,⁴ Center for Retrovirus Research,³ Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210⁵

Received 10 December 2001/ Returned for modification 26 February 2002/ Accepted 17 June 2002

In a previous study, zidovudine (ZDV) was shown to cause a concentration-dependent inhibition of antigen-specific cytotoxic T-lymphocyte (CTL) clonal expansion (S. Francke, C. G. Orosz, K. A. Hayes, and L. E. Mathes, Antimicrob. Agents Chemother. 44:1900-1905, 2000). However, this suppressive effect was lost if exposure to ZDV was delayed for 24 to 48 h during the antigen sensitization period, suggesting that antigen-primed CTL may be less susceptible than naive T lymphocytes to the suppressive effects of ZDV. The present study was undertaken to determine if naive T lymphocytes were more sensitive to the suppressive effects of ZDV than T lymphocytes previously exposed to antigen. The 50% inhibitory concentration (IC₅₀) values of ZDV were determined on naive and antigen-primed T-cell responses in an alloantigen system. Lymphocyte cultures with continuous antigen exposure (double prime) were more resistant to ZDV suppression (IC₅₀ = 316 µM) than were naive lymphocytes (IC₅₀ = 87.5 µM). Interestingly, lymphocytes that were antigen primed but deprived of antigen during the final 7 days of culture (prime/hold) were exquisitely sensitive to ZDV suppression (IC₅₀ = 29.3 µM). The addition of 80 µM ZDV during the initial priming of the single-prime (prime/hold) and double-prime cultures did not select for a more drug-resistant cell population. The differences in ZDV sensitivities are likely a reflection of the physiological properties of the lymphocytes related to their activation state.

Present address: DHHS/FDA/CFSAN, Pathology Branch HSF-716, Room 4E-008, 5100 Paint Branch Parkway, College Park, MD 20740-3835.