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Journal of Virology, August 2007, p. 8258-8269, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.02739-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Natural Variation in the V3 Crown of Human Immunodeficiency Virus Type 1 Affects Replicative Fitness and Entry Inhibitor Sensitivity{triangledown}

Michael A. Lobritz,1,2 Andre J. Marozsan,2 Ryan M. Troyer,2 and Eric J. Arts1,2*

Department of Molecular Biology and Microbiology,1 Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 441062

Received 12 December 2006/ Accepted 1 May 2007

Natural polymorphisms in the heterogeneous human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein may have an impact on both sensitivity to entry inhibitors and viral replicative fitness. Of significant interest is variation in the V3 crown due to its involvement in direct engagement with the coreceptor. Two positions in the crown (318 and 319) appear to be important in determining intrinsic susceptibility to multiple entry inhibitors. Thus, we evaluated a series of natural polymorphisms at positions 318 and 319 in three distinct CCR5-tropic envelope genetic backgrounds to address their role in replicative fitness and sensitivity to entry inhibitors. Change at position 319 to each of the three major consensus amino acids (A, T, and R) resulted in variation in sensitivity to entry inhibitors and altered replicative fitness, but the effects of any one amino acid depended on the envelope context. Change of the nearly invariant tyrosine at position 318 to a rare arginine resulted in increased sensitivity to entry inhibitors and decreased replicative fitness independent of envelope context. Polymorphisms in the V3 crown that showed increased susceptibility to entry inhibitors also exhibited decreased entry efficiency, replicative fitness in primary peripheral blood mononuclear cells, and ability to replicate in primary macrophages. These findings suggest that differences in coreceptor affinity and/or avidity may underlie these phenotypic characteristics.

* Corresponding author. Mailing address: Division of Infectious Diseases, BRB 1029, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Phone: (216) 368-8904. Fax: (216) 368-2034. E-mail: eja3{at}case.edu

{triangledown} Published ahead of print on 23 May 2007.

Journal of Virology, August 2007, p. 8258-8269, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.02739-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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