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Journal of Virology, May 2005, p. 5695-5704, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5695-5704.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cell Cycle Arrest in G2/M Promotes Early Steps of Infection by Human Immunodeficiency Virus

Bettina Groschel{dagger} and Frederic Bushman*

University of Pennsylvania School of Medicine Department of Microbiology, 3610 Hamilton Walk, Philadelphia, PA 19104-6076

Received 28 July 2004/ Accepted 15 December 2004

We have identified four small molecules that boost transduction of cells by human immunodeficiency virus (HIV) and investigated their mechanism of action. These molecules include etoposide and camptothecin, which induce DNA damage by inhibiting religation of cleaved topoisomerase-DNA complexes, taxol, which interferes with the function of microtubules, and aphidicolin, which inhibits DNA polymerases. All four compounds arrest the cell cycle at G2/M, though in addition high concentrations of aphidicolin arrest in G1. We find that early events of HIV replication, including synthesis of late reverse transcription products, two-long terminal repeat circles, and integrated proviruses, were increased after treatment of cells with concentrations of each compound that arrested in G2/M. Stimulation was seen for both transformed cell lines (293T and HeLa cells) and primary cells (IMR90 lung fibroblasts). Arrest in G1 with high concentrations of aphidicolin boosted transduction, though not much as with lower concentrations that arrested in G2/M. Arrest of IMR90 cells in G1 by serum starvation and contact inhibition reduced transduction. Previously, the proteasome inhibitor MG132 was reported to increase HIV infection—here we investigated the effects of combinations of the cell cycle inhibitors with MG132 and obtained data suggesting that MG132 may also boost transduction by causing G2/M cell cycle arrest. These data document that cell cycle arrest in G2/M boosts the early steps of HIV infection and suggests methods for increasing transduction with HIV-based vectors.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, Department of Microbiology, 3610 Hamilton Walk, Philadelphia, PA 19104-6076. Phone: (215) 573-8732. Fax: (215) 573-4856. E-mail: bushman{at}mail.med.upenn.edu.

{dagger} Present address: Infectious Disease Laboratory, The Salk Institute, 10010 North Torrey Pines Rd., La Jolla, CA 92037.

Journal of Virology, May 2005, p. 5695-5704, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5695-5704.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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