Human immunodeficiency virus type 1 glycoprotein 41 N-terminal heptad repeat (NHR)

The HIV-1 gp41 N-terminal heptad repeat (NHR) is a highly conserved domain within the transmembrane subunit of the HIV-1 envelope glycoprotein (Env) [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121182/]. It plays a pivotal role in the fusion of the viral envelope with the host cell membrane, a necessary step for viral entry and infection [PNAS, https://www.pnas.org/doi/10.1073/pnas.1013540108]. Following the binding of the gp120 subunit to CD4 and coreceptors, gp41 undergoes a conformational change that exposes the NHR, which then forms a stable trimeric coiled-coil [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121182/]. This NHR trimer acts as a scaffold for the C-terminal heptad repeat (CHR) regions to fold back and bind, creating a six-helix bundle (6-HB) that drives membrane apposition and fusion [MDPI, https://www.mdpi.com/1999-4915/11/9/811]. Therapeutic agents known as fusion inhibitors, such as the FDA-approved peptide enfuvirtide, target the NHR by mimicking the CHR and binding to the NHR trimer [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121182/]. This binding prevents the formation of the 6-HB, thereby blocking viral entry [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121182/]. However, the clinical utility of these drugs is often challenged by the emergence of resistance mutations within the NHR sequence and the requirement for parenteral administration [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121182/].

Other names

HR1N-heptad repeatN-terminal coiled-coilN-trimergp41 NHRN-terminal heptad repeat

Fusion inhibition by binding to the NHR trimer and preventing the formation of the six-helix bundle (6-HB) core [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121182/].