PuSH - Publikationsserver des Helmholtz Zentrums München: HIV-1 NEF and VPU interfere with L-selectin (CD62L) cell surface expression to inhibit adhesion and signaling in infected CD4<sup>+</sup> t lymphocytes.

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Vassena, L.* ; Giuliani, E.* ; Koppensteiner, H. ; Bolduan, S. ; Schindler, M. ; Doria, M.*

HIV-1 NEF and VPU interfere with L-selectin (CD62L) cell surface expression to inhibit adhesion and signaling in infected CD4⁺ t lymphocytes.

J. Virol. 89, 5687-5700 (2015)

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Leukocytes recirculation between blood and lymphoid tissues is required for the generation and maintenance of immune responses against pathogens and is crucially controlled by the L-selectin (CD62L) leukocyte homing receptor. CD62L has adhesion and signaling functions and initiates the capture and rolling on the vascular endothelium of cells entering peripheral lymph nodes. This study reveals that CD62L is strongly down-regulated on primary CD4(+) T lymphocytes upon infection with human immunodeficiency virus type 1 (HIV-1). Reduced cell-surface CD62L expression was attributable to the Nef and Vpu viral proteins and not due to increased shedding via matrix metalloproteases. Both Nef and Vpu associated with and sequestered CD62L in perinuclear compartments thereby impeding CD62L transport to the plasma membrane. Besides, Nef decreased total CD62L protein levels. Importantly, infection with wild type but not Nef- and Vpu-deficient HIV-1 inhibited the capacity of primary CD4(+) T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1 infection impaired the signaling pathways and co-stimulatory signals triggered in primary CD4(+) T cells by CD62L ligation. We propose that HIV-1 dysregulates CD62L expression to interfere with the trafficking and activation of infected T cells. Altogether, this novel HIV-1 function could contribute to virus dissemination and evasion of host immune responses. IMPORTANCE: L-selectin (CD62L) is an adhesion molecule that mediates the first steps of leukocytes homing to peripheral lymph nodes, thus crucially controlling the initiation and maintenance of immune responses against pathogens. Here we report that CD62L is down-modulated on the surface of HIV-1-infected T cells through the activity of two viral proteins, Nef and Vpu, that prevent newly synthesized CD62L molecules to reach the plasma membrane. We provide evidence that CD62L down-regulation on HIV-1-infected primary T cells results in impaired adhesion and signaling functions upon CD62L triggering. Removal of cell-surface CD62L may predictably keep HIV-1-infected cells away from lymph nodes, the privileged sites of both viral replication and immune response activation, with important consequences such as systemic viral spread and evasion of the host immune surveillance. Altogether, we propose that Nef- and Vpu-mediated subversion of CD62L function could represent a novel determinant of HIV-1 pathogenesis.

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PuSH - Publikationsserver des Helmholtz Zentrums München

HIV-1 NEF and VPU interfere with L-selectin (CD62L) cell surface expression to inhibit adhesion and signaling in infected CD4+ t lymphocytes.

HIV-1 NEF and VPU interfere with L-selectin (CD62L) cell surface expression to inhibit adhesion and signaling in infected CD4⁺ t lymphocytes.