Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: Role of a conserved hydrophobic cavity in membrane fusion

The gp41 envelope protein of human immunodeficiency virus type 1 (HIV-1) co ntains an alpha-helical core structure responsible for mediating membrane f usion during viral entry. Recent studies suggest that a conserved hydrophob ic cavity in the coiled coil of this core plays a distinctive structural ro le in maintaining the fusogenic conformation of the gp41 molecule. Here we investigated the importance of this cavity in determining the structure and hiological activity of the gp41 core by using the N34(L6)C28 model. The hi gh-resolution crystal structures of N34(L6)C28 of two HIV-1 gp41 fusion-def ective 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 mol ecule. The enhanced inhibitory activity by fusion-defective mutations corre lates with local structural perturbations close to the cavity that destabil ize the six-helix bundle, Taken together, these results indicate that the c onserved hydrophobic coiled-coil cavity in the gp41 core is critical for HI V-1 entry and its inhibition and provides a potential antiviral drug target .