%0 Journal Article
%A Quijada Freire, Adriana
%A Santiago, César A.
%A García Cuesta, Eva M.
%A Soler Palacios, Blanca
%A Ayala Bueno, Rosa
%A Gardeta, Sofia R.
%A San Sebastian, Enara
%A Armendariz Burgoa, Eva
%A Puertas, Maria Carmen
%A Villares, Ricardo
%A Garaigorta, Urtzi
%A González Granado, Luis Ignacio
%A Rodriguez Frade, Jose Miguel
%A Chojnacki, Jakub
%A Martínez Picado, Javier
%A Mellado, Mario
%T HIV-1 envelope glycoprotein modulates CXCR4 clustering and dynamics on the T cell membrane.
%D 2026
%@ 2050-084X
%U https://hdl.handle.net/20.500.14352/138102
%X HIV-1 entry into susceptible cells requires the dynamic interaction of its envelope (Env) glycoprotein with the host cell receptor CD4 and a co-receptor, either CCR5 or CXCR4. While the core molecular mechanisms driving Env-receptor interactions and subsequent membrane fusion are well characterized, the precise nanoscale spatial reorganization of these co-receptors at the viral binding site remains poorly defined. In this study, we employed single-particle tracking total internal reflection fluorescence (SPT-TIRF) microscopy to quantitatively analyze nanoscale organizational changes of CXCR4 on the surface of human CD4 T cells following binding by X4-tropic HIV-1. Our data reveal that both recombinant X4-gp120 and virus-like particles expressing physiological levels of X4 Env proteins (gp120 and gp41) promote CXCR4 clustering, a phenomenon linked to cell infection. Furthermore, these ligands induced oligomerization of CXCR4, a naturally occurring mutant associated with WHIM syndrome that supports HIV-1 infection, but fails to oligomerize in response to CXCL12. Our findings establish a link between CXCR4 clustering and HIV-1 infection, enhancing our understanding of the initial events in viral attachment and entry. These results further suggest that HIV-1 depends on a specific spatial arrangement of co-receptors, distinct from that induced by their natural chemokine ligands, highlighting the critical role of cell-surface receptor spatial organization in dictating cellular function.
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