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Journal of Virology, March 2003, p. 3167-3180, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3167-3180.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

As2O3 Enhances Retroviral Reverse Transcription and Counteracts Ref1 Antiviral Activity

Lionel Berthoux,1 Greg J. Towers,2 Cagan Gurer,1 Paolo Salomoni,3 Pier Paolo Pandolfi,3 and Jeremy Luban1,4*

Departments of Microbiology,1 Medicine, College of PhysiciansSurgeons, Columbia University, New York, New York 10032,4 Wohl Virion Centre, Windeyer Institute, University College London, W1T 4JF London, United Kingdom,2 Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, New York 100213

Received 28 August 2002/ Accepted 5 December 2002

Potent drugs such as cyclosporine have provided effective probes of signal transduction pathways and, as well, of human immunodeficiency virus type 1 (HIV-1) replication mechanisms. Recently, it was reported that As2O3, a drug used to treat acute promyelocytic leukemia (PML), stimulates HIV-1 replication. We found that As2O3 accelerates the kinetics of a spreading HIV-1 infection in human T cells and increases the number of cells bearing HIV-1 provirus after a single round of infection. The stimulatory effect occurred after membrane fusion and resulted in increased steady-state levels of newly synthesized viral cDNA. Stimulation was independent of HIV-1 env and most viral accessory genes, and As2O3 had no detectable effects on viral expression postintegration or virion assembly. Murine leukemia virus (MLV) transduction was enhanced by As2O3 to the same extent as HIV-1 transduction, but As2O3 had no additional effect on Fv1 restriction. In contrast, As2O3 largely overcame the specific block to N-tropic MLV reverse transcription posed by human Ref1. As2O3 disrupts PML bodies, nuclear structures named for a major component, the PML protein. We observed no changes in PML bodies in response to HIV-1 infection. Experiments with PML-null target cells indicated that PML has no effect on HIV-1 infectivity and is dispensable for the stimulatory effect of As2O3. As2O3 caused cell death in uninfected cells at the same concentrations which stimulate HIV-1 replication. Among four additional apoptosis-inducing agents, a boost in HIV-1 infectivity was observed only with carbonyl cyanide m-chlorophenylhydrazone, a compound which, like As2O3, disrupts the mitochondrial transmembrane potential. In summary, As2O3 stimulates retroviral reverse transcription, perhaps via effects on mitochondria, and provides a useful tool for characterizing Ref1.

* Corresponding author. Mailing address: Departments of Microbiology and Medicine, College of Physicians and Surgeons, Columbia University, 701 W. 168th St., New York, NY 10032. Phone: (212) 305-8706. Fax: (212) 305-0333. E-mail: JL45{at}columbia.edu.

Journal of Virology, March 2003, p. 3167-3180, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3167-3180.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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