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Journal of Virology, April 2007, p. 3749-3756, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02634-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Mutation in Alpha Helix 3 of CA Renders Human Immunodeficiency Virus Type 1 Cyclosporin A Resistant and Dependent: Rescue by a Second-Site Substitution in a Distal Region of CA{triangledown}

Ruifeng Yang and Christopher Aiken*

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee

Received 28 November 2006/ Accepted 22 January 2007

The replication of many isolates of human immunodeficiency virus type 1 (HIV-1) is enhanced by binding of the host cell protein cyclophilin A (CypA) to the viral capsid protein (CA). The immunosuppressive drug cyclosporine A (CsA) and its nonimmunosuppressive analogs bind with high affinity to CypA and inhibit HIV-1 replication. Previous studies have identified two mutations, A92E and G94D, in the CypA-binding loop of CA that confer the ability of HIV-1 to replicate in the presence of CsA. Interestingly, CsA stimulates the replication of HIV-1 mutants containing either the A92E or G94D substitution in some human cell lines. Here, we show that substitution of alanine for threonine at position 54 of CA (T54A) also confers HIV-1 resistance to and dependence on CsA. Like the previously identified CsA-resistant/dependent mutants, infection by the T54A mutant was stimulated by CsA in a target cell-specific manner. RNA interference-mediated reduction of CypA expression enhanced the permissiveness of HeLa cells to infection by the T54A mutant. A suppressor mutation, encoding a substitution of threonine for alanine at position 105 of CA (A105T), was identified through adaptation of the T54A mutant virus for growth in CEM cells. A105T rescued the impaired single-cycle infectivity and replication defects of both T54A and A92E mutants. These results indicate that CA determinants outside the CypA-binding loop can modulate the dependence of HIV-1 infection on CypA.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, A-5301 Medical Center North, Nashville, TN 37232-2363. Phone: (615) 343-7037. Fax: (615) 343-7392. E-mail: chris.aiken{at}vanderbilt.edu

{triangledown} Published ahead of print on 31 January 2007.

Journal of Virology, April 2007, p. 3749-3756, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02634-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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