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Journal of Virology, December 2005, p. 14815-14821, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14815-14821.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Effect of Cell Cycle Arrest on the Activity of Nucleoside Analogues against Human Immunodeficiency Virus Type 1

Sebastien Wurtzer,1 Séverine Compain,2 Henri Benech,2 Allan J. Hance,1 and François Clavel1*

Unité de Recherche Antivirale, Inserm U552, Hôpital Bichat-Claude Bernard, Paris, France,1 Laboratoire de Pharmacologie et d'Immunologie, CEA/Saclay, Gif sur Yvette, France2

Received 21 April 2005/ Accepted 7 September 2005

Human immunodeficiency virus (HIV) reverse transcription can be notably affected by cellular activation, differentiation, and division. We hypothesized that changes in the cell cycle could also affect HIV susceptibility to nucleoside analogues, which compete with natural nucleotides for incorporation into viral DNA and inhibit viral replication through premature termination of reverse transcription. Proliferating HeLa-derived indicator cells were arrested in the S/G2 phase with etoposide, a topoisomerase II inhibitor, or in the G1/S phase with aphidicolin, a polymerase {alpha} inhibitor. Cell cycle arrest by both agents induced a remarkable decrease in HIV susceptibility to zidovudine (AZT). This decrease was seen both with a single-cycle infectivity assay and with a viral DNA quantitation assay, indicating that the effect of cell cycle arrest was exerted at the reverse transcription stage. The increase in the 50% inhibitory concentration (IC50) seen with arrested cells was strongest for AZT (23-fold) and stavudine (21-fold) but more modest for other drugs (lamivudine, 11-fold; dideoxyinosine, 7-fold; and nevirapine, 3-fold). In drug-resistant reverse transcriptase mutants, the increase in AZT IC50 (relative to that in dividing cells) was most prominent with a Q151M mutant and was comparable to the wild type in other drug-resistant mutants. Quantitation of intracellular pools of dTTP and AZT 5'-triphosphate (AZTTP) showed that etoposide treatment induced a significant increase in intracellular dTTP and consequently a decrease in AZTTP/dTTP ratios, suggesting that the decrease in viral susceptibility to AZT was caused by reduced incorporation of the analogue into nascent viral DNA. These results emphasize the importance of cellular proliferation and deoxynucleoside triphosphate metabolism in HIV susceptibility to nucleoside analogues and underscore the need to study the activities of drugs of this class with natural target cells under physiological conditions of activation and proliferation.

* Corresponding author. Mailing address: Inserm U552, IMEA, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. Phone: 331 4025 6363. Fax: 331 4025 6351. E-mail: clavel{at}bichat.inserm.fr.

Journal of Virology, December 2005, p. 14815-14821, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14815-14821.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Luber, A. D. (2008). Pharmacokinetic Considerations for Selection of HAART in Treatment-Naive HIV-Infected Individuals, 2008: More Than It Seems?. J Int Assoc Physicians AIDS Care (Chic Ill) 7: 10-16 [Abstract]  
  • Durand-Gasselin, L., Da Silva, D., Benech, H., Pruvost, A., Grassi, J. (2007). Evidence and Possible Consequences of the Phosphorylation of Nucleoside Reverse Transcriptase Inhibitors in Human Red Blood Cells. Antimicrob. Agents Chemother. 51: 2105-2111 [Abstract] [Full Text]  
  • Benech, H., Becher, F., Pruvost, A., Grassi, J. J., Melendez, M., Rodriguez, J. F. (2006). Is Stavudine triphosphate a natural metabolite of Zidovudine?. Antimicrob. Agents Chemother. 50: 2899-2901 [Full Text]  


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