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Journal of Virology, April 2009, p. 3798-3809, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01751-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Characterization of a Human Immunodeficiency Virus Type 1 V3 Deletion Mutation That Confers Resistance to CCR5 Inhibitors and the Ability To Use Aplaviroc-Bound Receptor {triangledown}

Katrina M. Nolan, Gregory Q. Del Prete, Andrea P. O. Jordan, Beth Haggarty, Josephine Romano, George J. Leslie, and James A. Hoxie*

Department of Medicine, Hematology-Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 19 August 2008/ Accepted 25 January 2009

The human immunodeficiency virus type 1 (HIV-1) V3 loop is essential for coreceptor binding and principally determines tropism for the CCR5 and CXCR4 coreceptors. Using the dual-tropic virus HIV-1R3A, we previously made an extensive panel of V3 deletions and identified subdomains within V3 that could differentially mediate R5 and X4 tropism. A deletion of residues 9 to 12 on the N-terminal side of the V3 stem ablated X4 tropism while leaving R5 tropism intact. This mutation also resulted in complete resistance to several small-molecule CCR5 inhibitors. Here, we extend these studies to further characterize a variant of this mutant, {Delta}9-12a, adapted for growth in CCR5+ SupT1 cells. Studies using coreceptor chimeras, monoclonal antibodies directed against the CCR5 amino terminus (NT) and extracellular loops, and CCR5 point mutants revealed that, relative to parental R3A, R5-tropic {Delta}9-12a was more dependent on the CCR5 NT, a region that contacts the gp120 bridging sheet and V3 base. Neutralization sensitivity assays showed that, compared to parental R3A, {Delta}9-12a was more sensitive to monoclonal antibodies b12, 4E10, and 2G12. Finally, cross-antagonism assays showed that {Delta}9-12a could use aplaviroc-bound CCR5 for entry. These studies indicate that increased dependence on the CCR5 NT represents a mechanism by which HIV envelopes acquire resistance to CCR5 antagonists and may have more general implications for mechanisms of drug resistance that arise in vivo. In addition, envelopes such as {Delta}9-12a may be useful for developing new entry inhibitors that target the interaction of gp120 and the CCR5 NT.

* Corresponding author. Mailing address: University of Pennsylvania, 356 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-0261. Fax: (215) 573-7356. E-mail: hoxie{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, April 2009, p. 3798-3809, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01751-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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