Nature 565, 318–323 (2019)

The ability of HIV-1 to infect human T cells requires interactions between the viral envelope (Env) fusion protein and primary receptor CD4 and co-receptors CCR5 and/or CXCR4 of the host. Binding of CD4 to the gp120 fragment of Env leads to conformational changes that allow binding to the co-receptor as well as refolding of the fusogenic gp41 fragment to induce virus–host cell fusion. To better understand how CCR5 functions as an HIV co-receptor, Shaik et al. solved a cryo-EM structure of a CD4–gp120–CCR5 complex. This revealed a CD4-induced gp120 conformation that allows two major contacting interfaces between gp120 and CCR5, one contributing to the high affinity of Env for CCR5, and another interface characterized by at least one cation–π interaction with sulfated CCR5 tyrosines. Though the authors could not identify any allosteric changes propagating from gp120 to gp41, they proposed that gp120 dissociation is critical for initiating gp41 refolding events preceding its insertion into target membranes. These results suggest a model in which CCR5 is responsible for stabilizing CD4-induced gp120 conformational changes bringing gp41 in close proximity to the target membrane to induce fusion.

Credit: Bing Chen