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Journal of Virology, September 2007, p. 9956-9966, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00385-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Replication-Competent Variants of Human Immunodeficiency Virus Type 2 Lacking the V3 Loop Exhibit Resistance to Chemokine Receptor Antagonists{triangledown}

George Lin,1 Andrea Bertolotti-Ciarlet,2 Beth Haggarty,1 Josephine Romano,1 Katrina M. Nolan,1 George J. Leslie,1 Andrea P.-O. Jordan,1 Chih-chin Huang,3 Peter D. Kwong,3 Robert W. Doms,2 and James A. Hoxie1*

Departments of Medicine,1 Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,2 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208923

Received 22 February 2007/ Accepted 23 June 2007

Entry of human immunodeficiency virus type 1 (HIV-1) and HIV-2 requires interactions between the envelope glycoprotein (Env) on the virus and CD4 and a chemokine receptor, either CCR5 or CXCR4, on the cell surface. The V3 loop of the HIV gp120 glycoprotein plays a critical role in this process, determining tropism for CCR5- or CXCR4-expressing cells, but details of how V3 interacts with these receptors have not been defined. Using an iterative process of deletion mutagenesis and in vitro adaptation of infectious viruses, variants of HIV-2 were derived that could replicate without V3, either with or without a deletion of the V1/V2 variable loops. The generation of these functional but markedly minimized Envs required adaptive changes on the gp120 core and gp41 transmembrane glycoprotein. V3-deleted Envs exhibited tropism for both CCR5- and CXCR4-expressing cells, suggesting that domains on the gp120 core were mediating interactions with determinants shared by both coreceptors. Remarkably, HIV-2 Envs with V3 deletions became resistant to small-molecule inhibitors of CCR5 and CXCR4, suggesting that these drugs inhibit wild-type viruses by disrupting a specific V3 interaction with the coreceptor. This study represents a proof of concept that HIV Envs lacking V3 alone or in combination with V1/V2 that retain functional domains required for viral entry can be derived. Such minimized Envs may be useful in understanding Env function, screening for new inhibitors of gp120 core interactions with chemokine receptors, and designing novel immunogens for vaccines.

* Corresponding author. Mailing address: Room 356, Biomedical Research Building II/III, University of Pennsylvania, 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 3 July 2007.

Journal of Virology, September 2007, p. 9956-9966, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00385-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nolan, K. M., Del Prete, G. Q., Jordan, A. P. O., Haggarty, B., Romano, J., Leslie, G. J., Hoxie, J. A. (2009). 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. J. Virol. 83: 3798-3809 [Abstract] [Full Text]  
  • Anastassopoulou, C. G., Ketas, T. J., Klasse, P. J., Moore, J. P. (2009). Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. Proc. Natl. Acad. Sci. USA 106: 5318-5323 [Abstract] [Full Text]  
  • Harrison, J. E., Lynch, J. B., Sierra, L.-J., Blackburn, L. A., Ray, N., Collman, R. G., Doms, R. W. (2008). Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100. J. Virol. 82: 11695-11704 [Abstract] [Full Text]  
  • Nolan, K. M., Jordan, A. P. O., Hoxie, J. A. (2008). Effects of Partial Deletions within the Human Immunodeficiency Virus Type 1 V3 Loop on Coreceptor Tropism and Sensitivity to Entry Inhibitors. J. Virol. 82: 664-673 [Abstract] [Full Text]  


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