anti-gp41 (HIV), mAb (rec.) (A2)

HIV-1 Env consists of two subunits: the surface-exposed glycoprotein gp120, which contains the receptor (CD4) and coreceptor (CCR5 or CXCR4) binding sites, and the transmembrane subunit gp41, which is critical for virus-cell membrane fusion. Sequential binding of HIV-1 to its receptor and coreceptor are the first steps critical for viral entry, whereby CD4 binding triggers a series of conformational changes in Env involving both gp120 and gp41. In gp120, CD4 binding induces rearrangement of the variable loops V1/V2 and formation of the bridging sheet, which allows for repositioning of the V3 loop to facilitate coreceptor binding. In gp41, CD4 binding triggers exposure of the buried N-terminal HR1 domain and its formation into a trimeric coiled-coil structure. Upon receptor and coreceptor binding, the fusion peptide in gp41 is inserted into the cell membrane and the HR1 and HR2 regions rearrange to form the six-helix bundle, which is critical for creation of the fusion pore to enable membrane fusion and efficient viral entry. The antibody clone A2 was found to specifically target the pocket-binding domain of gp41 CHR when CHRs maintain in the trimer conformation.