HIV-1 gp41 N-terminal heptad repeat region (NHR)

The HIV-1 gp41 N-terminal heptad repeat (NHR) region, also known as HR1, is a critical functional domain of the gp41 transmembrane glycoprotein, which mediates the fusion of the HIV-1 viral envelope with the host cell membrane [5, 6]. Following the binding of the viral gp120 subunit to the host CD4 receptor and a co-receptor (CCR5 or CXCR4), gp41 undergoes a dramatic conformational change, exposing the NHR and CHR (C-terminal heptad repeat) regions [11, 14]. The NHR region forms a central trimeric coiled-coil that serves as a scaffold for the CHR helices to fold back upon, creating a stable six-helix bundle (6-HB) that pulls the membranes together for fusion [5, 14]. This region is the primary target for fusion inhibitors like enfuvirtide (T-20), which bind to the NHR during the transient pre-hairpin intermediate state to block 6-HB formation and prevent viral entry [1, 7]. Therapeutic targeting of the NHR is a validated strategy for treating HIV-1 infection, particularly in treatment-experienced patients [1, 13]. However, challenges such as the requirement for parenteral administration and the emergence of resistance mutations within the NHR sequence remain significant [1, 13, 17]. Next-generation inhibitors targeting the NHR pocket are being developed to improve potency and overcome resistance [7, 10]. The NHR is also a target for research into broadly neutralizing antibodies and therapeutic vaccines [5, 8].

Other names

HR1N-terminal heptad repeatN-heptad repeatHeptad repeat 1N-terminal alpha-helical leucine zipper-like heptad repeat

Fusion inhibition by binding to the N-terminal heptad repeat (NHR) during the pre-hairpin intermediate state, preventing the formation of the six-helix bundle (6-HB) required for viral and host cell membrane fusion [1, 5, 14].