2026-07-31T09:26:55Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1381022026-07-08T00:02:21Zcom_20.500.14352_14col_20.500.14352_15

HIV-1 envelope glycoprotein modulates CXCR4 clustering and dynamics on the T cell membrane. Quijada Freire, Adriana Santiago, César A. García Cuesta, Eva M. Soler Palacios, Blanca Ayala Bueno, Rosa Gardeta, Sofia R. San Sebastian, Enara Armendariz Burgoa, Eva Puertas, Maria Carmen Villares, Ricardo Garaigorta, Urtzi González Granado, Luis Ignacio Rodriguez Frade, Jose Miguel Chojnacki, Jakub Martínez Picado, Javier Mellado, Mario 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. 2026-07-07T10:43:05Z 2026-07-07T10:43:05Z 2026-07-07T10:43:05Z 2026-05-12 journal article https://hdl.handle.net/20.500.14352/138102 2050-084X 10.7554/eLife.110354.2 eng Quijada-Freire A, Santiago CA, García-Cuesta EM, Soler Palacios B, Ayala-Bueno R, Gardeta SR, San Sebastian E, Armendariz-Burgoa E, Puertas MC, Villares R, Garaigorta U, González-Granado LI, Rodriguez Frade JM, Chojnacki J, Martinez-Picado J, Mellado M. HIV-1 envelope glycoprotein modulates CXCR4 clustering and dynamics on the T cell membrane. eLife. 2026;15:RP110354. doi: 10.7554/eLife.110354. PMCID: PMC13167113. http://creativecommons.org/licenses/by/4.0/ open access Attribution 4.0 International eLife Sciences Publications Ltd.