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Journal of Virology, November 2004, p. 12066-12070, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.12066-12070.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Selection for Loss of Ref1 Activity in Human Cells Releases Human Immunodeficiency Virus Type 1 from Cyclophilin A Dependence during Infection

David M. Sayah1 and Jeremy Luban1,2*

Departments of Microbiology,1 Medicine, Columbia University College of Physicians and Surgeons, New York, New York2

Received 15 April 2004/ Accepted 21 June 2004

Capsid (CA)-specific restrictions are determinants of retroviral tropism in mammalian cells. One such restriction, human Ref1, targets strains of murine leukemia virus bearing an arginine at CA residue 110 (N-MLV), resulting in decreased accumulation of viral cDNA. The cellular factors accounting for Ref1 activity are unknown. As2O3 increases N-MLV titer in Ref1-positive cells, possibly by counteracting Ref1. Restriction factor saturation experiments suggest that Ref1 may also target human immunodeficiency virus type 1 (HIV-1), but only if its CA is not bound to the cellular protein cyclophilin A (CypA). As a step towards understanding the genetic determinants of Ref1, we subjected Ref1-positive TE671 cells to three sequential rounds of selection with N-MLV reporter viruses. We isolated a subclone, 17H1, that was permissive for N-MLV infection and therefore deficient in Ref1 activity. Stimulation of N-MLV replication by As2O3 was attenuated in 17H1, confirming that the drug acts by overcoming Ref1 activity. HIV-1 infection of 17H1 cells was resistant to disruption of the CA-CypA interaction, demonstrating that Ref1 restricts CypA-free HIV-1. Our results suggest that interaction with CypA evolved to protect HIV-1 from this human antiviral activity.

* Corresponding author. Mailing address: Microbiology Department, 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, November 2004, p. 12066-12070, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.12066-12070.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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