Lafrenie R M, Wahl L M, Epstein J S, Hewlett I K, Yamada K M, Dhawan S
Laboratory of Developmental Biology, National Institute of Dental Research, Bethesda, MD 20892, USA.
J Immunol. 1996 Feb 15;156(4):1638-45.
Monocytes are major targets of HIV infection in patients with AIDS. In vitro infection of monocytes with HIV is associated with increased expression of beta 2 integrins, which increases both monocyte aggregation and monocyte/endothelial adhesion as well as monocyte metalloproteinase (MMP-9) expression. Treatment of primary monocytes with soluble HIV-Tat protein mimicked many of the properties of HIV infection of monocytes. Tat treatment up-regulated the expression of the beta 2 integrins, which was associated with the formation of large aggregates of monocytes and increased adhesion to endothelial monolayers. Treatment of monocytes with Tat increased their adhesion to both untreated and TNF-alpha-treated endothelial monolayers, and adhesion was inhibited by inclusion of anti-beta 2 and anti-ICAM-1 Abs. The increased adhesion of activated monocytes was accompanied by substantial disruption of the endothelial monolayers, with retraction or detachment of individual endothelial cells. Tat treatment of monocytes up-regulated the synthesis and release of the protease MMP-9, providing a potential mechanism to explain endothelial cell/basement membrane detachment. Thus, extracellular Tat is capable of activating monocytes even in the absence of HIV infection. Our studies demonstrate that many of the effects of HIV infection on monocyte homotypic and heterotypic adhesion, protease secretion, and disruption of the endothelium can be mimicked by treatment with HIV-Tat protein alone. These results suggest a mechanism where monocytes could be inappropriately activated by HIV-Tat, secreted by HIV-infected cells, causing them to extravasate into underlying tissues and ultimately contribute to tissue damage as seen during the progression of AIDS.
单核细胞是艾滋病患者中HIV感染的主要靶细胞。HIV在体外感染单核细胞会导致β2整合素表达增加，这会使单核细胞聚集增加、单核细胞与内皮细胞的黏附增加以及单核细胞金属蛋白酶（MMP - 9）表达增加。用可溶性HIV - Tat蛋白处理原代单核细胞可模拟HIV感染单核细胞的许多特性。Tat处理上调了β2整合素的表达，这与单核细胞形成大聚集体以及对内皮细胞单层黏附增加有关。用Tat处理单核细胞会增加其对未处理的和经TNF -α处理的内皮细胞单层的黏附，并且加入抗β2和抗ICAM - 1抗体可抑制黏附。活化单核细胞黏附增加伴随着内皮细胞单层的大量破坏，单个内皮细胞出现回缩或脱离。用Tat处理单核细胞上调了蛋白酶MMP - 9的合成和释放，这为解释内皮细胞/基底膜脱离提供了一种潜在机制。因此，即使在没有HIV感染的情况下，细胞外Tat也能够激活单核细胞。我们的研究表明，HIV感染对单核细胞同型和异型黏附以及蛋白酶分泌和内皮破坏的许多影响，仅用HIV - Tat蛋白处理即可模拟。这些结果提示了一种机制，即HIV感染细胞分泌的HIV - Tat可能会不恰当地激活单核细胞，导致它们渗出到下层组织中，并最终在艾滋病进展过程中导致组织损伤。
