Human immunodeficiency virus type 1 glycoprotein 41 N-terminal heptad repeat hydrophobic pocket (HIV-1 gp41 NHR hydrophobic pocket)

The HIV-1 gp41 N-terminal heptad repeat (NHR) hydrophobic pocket is a highly conserved structural domain within the transmembrane subunit of the HIV-1 envelope glycoprotein (gp41). It plays a pivotal role during the fusion of the viral envelope with the host cell membrane, a process triggered by the binding of gp120 to CD4 and coreceptors (Chan et al., 1997). Upon activation, gp41 transitions into a pre-hairpin intermediate where three NHR segments form a central trimeric coiled-coil, creating a deep hydrophobic groove or pocket. This pocket serves as a critical docking site for the C-terminal heptad repeat (CHR) region; their interaction forms a stable six-helix bundle (6HB) that drives membrane apposition and fusion (Root et al., 2001). Because this pocket is essential for viral infectivity and highly conserved across diverse HIV-1 strains, it is a primary target for the development of fusion inhibitors. Drugs targeting this site, such as the peptide-based inhibitor Albuvirtide or experimental agents like T-1249, bind to the NHR coiled-coil and prevent the transition to the fusion-active state (Liu et al., 2007). This mechanism effectively halts the entry of HIV-1 into host CD4+ T cells, providing a therapeutic option for patients with multi-drug resistant infections.

Other names

gp41 hydrophobic pocketNHR hydrophobic pocketgp41 N-terminal heptad repeat pocketHIV-1 gp41 fusion pocketgp41 NHR groove

Inhibition of viral-cell membrane fusion by binding to the N-terminal heptad repeat (NHR) region of gp41, thereby preventing the formation of the six-helix bundle (6HB) required for entry.