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Journal of Virology, October 1999, p. 8578-8586, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Infectivity by the gp41 Core: Role of a Conserved Hydrophobic Cavity in Membrane Fusion

Hong Ji,1 Wei Shu,1 F. Temple Burling,1 Shibo Jiang,2 and Min Lu1,*

Department of Biochemistry, Weill Medical College of Cornell University,1 and Lindsley F. Kimball Research Institute, New York Blood Center,2 New York, New York 10021

Received 19 January 1999/Accepted 14 June 1999

The gp41 envelope protein of human immunodeficiency virus type 1 (HIV-1) contains an alpha -helical core structure responsible for mediating membrane fusion during viral entry. Recent studies suggest that a conserved hydrophobic cavity in the coiled coil of this core plays a distinctive structural role in maintaining the fusogenic conformation of the gp41 molecule. Here we investigated the importance of this cavity in determining the structure and biological activity of the gp41 core by using the N34(L6)C28 model. The high-resolution crystal structures of N34(L6)C28 of two HIV-1 gp41 fusion-defective mutants reveal that each mutant sequence is accommodated in the six-helix bundle structure by forming the cavity with different sets of atoms. Remarkably, the mutant N34(L6)C28 cores are highly effective inhibitors of HIV-1 infection, with 5- to 16-fold greater activity than the wild-type molecule. The enhanced inhibitory activity by fusion-defective mutations correlates with local structural perturbations close to the cavity that destabilize the six-helix bundle. Taken together, these results indicate that the conserved hydrophobic coiled-coil cavity in the gp41 core is critical for HIV-1 entry and its inhibition and provides a potential antiviral drug target.

* Corresponding author. Mailing address: Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Phone: (212) 746-6562. Fax: (212) 746-8875. E-mail: mlu{at}mail.med.cornell.edu.

Journal of Virology, October 1999, p. 8578-8586, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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