CXCR4 mediated recognition of HIV envelope spike and inhibition by CXCL12

Zhiying Zhang (), Hongwei Zhang, Lyuqin Zheng, Shihua Chen, Shuo Du, Junyu Xiao () and Dinshaw J. Patel ()
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Zhiying Zhang: Memorial Sloan-Kettering Cancer Center
Hongwei Zhang: Memorial Sloan-Kettering Cancer Center
Lyuqin Zheng: Memorial Sloan-Kettering Cancer Center
Shihua Chen: Peking University
Shuo Du: Peking University
Junyu Xiao: Peking University
Dinshaw J. Patel: Memorial Sloan-Kettering Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract CCR5 and CXCR4 both act as HIV co-receptors, though CXCR4 is less explored. CXCR4 binds the chemokine CXCL12 to regulate cellular processes and mediate HIV entry, a process that CXCL12 inhibits. Using cryo-EM, we investigate HIV-2 envelope (Env) spike recognition by CXCR4 and how CXCL12 inhibit this interaction. We discover that CXCR4 unexpected forms a tetramer, both alone and in complex. It binds CXCL12 with 4:8 and 8:8 stoichiometries, with the CXCL12 N-terminus inserting into the CXCR4 pocket. Structures of CXCR4-gp120HIV-2 complex show one or two gp120 molecules per CXCR4 tetramer, with the V3 loop occupying the major sub-pocket of CXCR4 through deep embedment of its GFKF motif. The CXCL12 N-terminus chashes with gp120HIV-2 V3 loops, explain its inhibitory effect. Docking analyses of other HIV antagonists further clarify their mechanisms. The CXCR4-gp120HIV-1 model illustrate how V3 loop residues define co-receptor specificity, offering insights into co-receptor switching and therapeutic design.

Date: 2025
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DOI: 10.1038/s41467-025-63815-2

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