Quaranta Maria Giovanna, Tritarelli Elena, Giordani Luciana, Viora Marina
Laboratory of Immunology, Istituto Superiore di Sanità, Rome, 00161, Italy.
Exp Cell Res. 2002 May 1;275(2):243-54. doi: 10.1006/excr.2002.5497.
Human immunodeficiency virus (HIV)-1 Nef protein is an essential modulator of AIDS pathogenesis and we have previously demonstrated that rNef enters uninfected human monocytes and induces T cells bystander activation, up-regulating IL-15 production. Since dendritic cells (DCs) play a central role in HIV-1 primary infection we investigated whether rNef affects DCs phenotypic and functional maturation in order to define its role in the immunopathogenesis of AIDS. We found that rNef up-regulates the expression on immature DCs of surface molecules known to be critical for their APC function. These molecules include CD1a, HLA-DR, CD40, CD83, CXCR4, and to a lower extent CD80 and CD86. On the other hand, rNef down-regulates surface expression of HLA-ABC and mannose receptor. The functional consequence of rNef treatment of immature DCs is a decrease in their endocytic and phagocytic activities and an increase in cytokine (IL-1beta, IL-12, IL-15, TNF-alpha) and chemokine (MIP-1alpha, MIP-1beta, IL-8) production as well as in their stimulatory capacity. These results indicate that rNef induces a coordinate series of phenotypic and functional changes promoting DC differentiation and making them more competent APCs. Indeed, Nef induces CD4(+) T cell bystander activation by a novel mechanism involving DCs, thus promoting virus dissemination.
人类免疫缺陷病毒1型（HIV-1）Nef蛋白是艾滋病发病机制的重要调节因子，我们之前已经证明重组Nef蛋白（rNef）可进入未感染的人类单核细胞并通过上调白细胞介素15（IL-15）的产生诱导旁观者T细胞激活。由于树突状细胞（DC）在HIV-1原发性感染中起核心作用，我们研究了rNef是否影响DC的表型和功能成熟，以确定其在艾滋病免疫发病机制中的作用。我们发现rNef上调了未成熟DC表面分子的表达，这些分子对其抗原呈递细胞（APC）功能至关重要。这些分子包括CD1a、人类白细胞抗原DR（HLA-DR）、CD40、CD83、CXC趋化因子受体4（CXCR4），以及程度较低的CD80和CD86。另一方面，rNef下调了HLA-ABC和甘露糖受体的表面表达。rNef处理未成熟DC的功能后果是其胞吞和吞噬活性降低，细胞因子（IL-1β、IL-12、IL-15、肿瘤坏死因子-α）和趋化因子（巨噬细胞炎性蛋白-1α、巨噬细胞炎性蛋白-1β、IL-8）的产生增加，以及其刺激能力增强。这些结果表明，rNef诱导了一系列协调的表型和功能变化，促进DC分化并使其成为更有能力的APC。事实上，Nef通过一种涉及DC的新机制诱导CD4⁺T细胞旁观者激活，从而促进病毒传播。
