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Journal of Virology, April 2009, p. 2989-2995, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02496-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide {triangledown}

Neelanjana Ray, Leslie A. Blackburn, and Robert W. Doms*

Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 4 December 2008/ Accepted 30 December 2008

Enfuvirtide (ENF) prevents the entry of human immunodeficiency virus type 1 (HIV-1) into cells by binding to the HR-1 region of the viral envelope (Env) protein gp41 subunit. Resistance to ENF arises via mutations in the drug binding site in HR-1. In addition, HR-2 mutations are commonly observed in ENF-resistant Env proteins, though their role remains unclear. We explored the mechanistic basis for clinical resistance to ENF and the role of HR-2 mutations. Using panels of ENF resistance-associated mutants for two patients, we found that mutations in HR-1 slowed the fusion kinetics and that mutations in HR-2 restored fusion rates. We assessed the differences in the rates of fusion of these mutants from a temperature-arrested state and observed similar trends, suggesting that the step of delay occurs after coreceptor engagement. Sensitivity to neutralizing antibodies was unchanged by the HR-1 and HR-2 mutants in each panel. Since this result was in contrast to those of a previous in vitro analysis where enhanced sensitivity to neutralization was demonstrated for heterologous Envs with ENF resistance-associated HR-1 changes, we examined the context dependence of HR-1 and HR-2 mutations by transferring the mutations seen in one patient into the Env context of another. These studies revealed that some, but not all, HR-1 mutations, when placed out of context (i.e., in a patient Env where they did not originally arise), enhance sensitivity to neutralizing antibodies. However, in most cases, HR-1 mutations in ENF-treated patients evolve in a manner that preserves pretreatment neutralization sensitivity so as to evade the pressures of the immune system.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania, 225 Johnson Pavilion, Philadelphia, PA 19104. Phone: (215) 573-6780. Fax: (215) 898-9557. E-mail: doms{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 19 January 2009.

Journal of Virology, April 2009, p. 2989-2995, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02496-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pan, C., Cai, L., Lu, H., Qi, Z., Jiang, S. (2009). Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains. J. Virol. 83: 7862-7872 [Abstract] [Full Text]  


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