Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer.
Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1-Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurred after the mutation of CD4 residues that interact with CD4-BS2. Our results document the critical role of quaternary interactions in the initial HIV-Env-receptor contact, with implications for treatment and vaccine design.
Liu, Q; Acharya, P; Dolan, MA; Zhang, P; Guzzo, C; Lu, J; Kwon, A; Gururani, D; Miao, H; Bylund, T; Chuang, G-Y; Druz, A; Zhou, T; Rice, WJ; Wigge, C; Carragher, B; Potter, CS; Kwong, PD; Lusso, P
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