Human immunodeficiency virus type 1 envelope glycoprotein gp41 heptad repeat 1 domain (HIV-1 gp41 HR1)

The Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 heptad repeat 1 (HR1) domain is a critical alpha-helical region within the gp41 transmembrane subunit (UniProt P04578) [1]. Following the binding of gp120 to host CD4 receptors and co-receptors, gp41 undergoes a conformational change where the HR1 domain interacts with the heptad repeat 2 (HR2) domain to form a stable six-helix bundle (6HB) (PubMed 9150141) [2]. This structural transition brings the viral and cellular membranes into close proximity, facilitating membrane fusion and the subsequent entry of the viral capsid into the host cell (PubMed 7914662) [3]. The HR1 domain is the primary target for fusion inhibitors like enfuvirtide, which is a synthetic peptide derived from the HR2 sequence (DrugBank DB00102) [4]. Enfuvirtide binds to the hydrophobic grooves of the HR1 trimer, preventing the formation of the 6HB and effectively blocking viral entry (PubMed 12626619) [5]. Therapeutic challenges include the development of resistance through mutations in the HR1 region, such as at positions 36 to 45, and the necessity for subcutaneous administration, which often leads to injection site reactions (PubMed 15104534) [7].

Other names

HR1 domainN-terminal heptad repeatN-HRgp41 HR1 regionHeptad repeat 1 of gp41

Fusion inhibition by binding to the HR1 domain to prevent the formation of the six-helix bundle (6HB) required for viral-host membrane fusion (PubMed 12626619) [5].