Nef 和Vpu,小小蛋白的大大梦想

marine0425030

最新一期的JVI，意大利和德国科研人员发表了一篇关于Nef 和Vpu蛋白对T细胞表面CD62L表达影响的研究。CD62L的作用可以参考 http://myx.js.zwu.edu.cn/show.asp?id=2804
Nef蛋白研究的比较多的下调CD4,MHC class I，提高感染率。 Vpu 的主要是促进病毒的装配和释放。
对了CD62L，我比较熟悉的功能是，CD62L主要在细胞归巢，该CD62L在central memory 细胞表面表达量高，在effector memory 表达量较低。
Nef 和Vpu蛋白下调CD62L的话，那么对central memory的分化和归巢肯定会有很大影响。



J Virol. 2015 Mar 11. pii: JVI.00611-15. [Epub ahead of print]
HIV-1 NEF AND VPU INTERFERE WITH L-SELECTIN (CD62L) CELL SURFACE EXPRESSION TO INHIBIT ADHESION AND SIGNALING IN INFECTED CD4+ T LYMPHOCYTES.


Vassena L, Giuliani E, Koppensteiner H2, Bolduan S2, Schindler M3, Doria M

Abstract

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-1inhibited the capacity of primary CD4+ T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1infection impaired the signaling pathways and co-stimulatory signals triggered in primary CD4+ T cells by CD62L ligation. We propose thatHIV-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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