Induction of lymphomonocyte activation by HIV-1 glycoprotein gp120. Possible role in AIDS pathogenesis.
Induction of lymphomonocyte activation by HIV-1 glycoprotein gp120. Possible role in AIDS pathogenesis.
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HIV-1 糖蛋白 gp120 诱导淋巴细胞活化。
DOI：
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发表时间：
1996
影响因子：
3.2
通讯作者：
M. Capobianchi
中科院分区：
文献类型：
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作者：
M. Capobianchi
细胞因子分泌模式的功能障碍已被认为在HIV感染的免疫发病机制中发挥核心作用。事实上，在经历疾病进展的HIV-1感染受试者中已经观察到T辅助细胞功能从Th 1型向TH 0型或TH 2型的转变。细胞因子网络的吸入伴随着免疫系统的持续激活、启动适当激活反应的能力受损（无反应性）和引发细胞凋亡。在过去的十年中，已经对HIV-1 gp 120或其前体gp 160对几种淋巴细胞和单核细胞功能的影响进行了广泛的研究。Gp 120能够升高细胞内钙浓度并诱导三磷酸肌醇的形成，能够阻断促分裂原或抗原驱动的T细胞活化，能够通过活化的PBMC亚群诱导改变的细胞因子产生，确定受损的细胞毒性和对抗原的趋化反应，干扰抗原呈递细胞的活性，增强或诱导凋亡，刺激多克隆B细胞活化并诱导或上调多种细胞因子，包括IL-6。TNF、IL-1-α和IL-1-β、IL-10和IL-8。此外，IFN-α和IFN-γ以及IFN活性的几种标志物，如β 2-微球蛋白和新蝶呤，在gp 120刺激的PBMC中诱导。然而，IL-4（Th 2型）和IL-2（Th 1型）以及DNA合成均不被gp 120激活。另一方面，gp 120刺激的PBMC表达增加的IL-2受体，并且可以被外源性IL-2诱导增殖，表明它们处于至少部分活化的状态。根据这一假设，其他活化标志物，早期（如CD 69）和晚期（如CD 45 RO和CD 71），都是由gp 120诱导的，但即使是部分活化也不会导致PBMC支持HIV-1的生产性感染的能力，除非存在外源性IL-2。HIV诱导的细胞因子可以通过上调或下调病毒复制直接影响HIV感染，或者通过调节细胞分子的表达间接影响HIV感染。事实上，在出芽过程中，HIV包膜捕获许多细胞膜蛋白，包括细胞因子受体如IL-2 R，粘附分子如LFA-1，ICAM-1，-2，HLA I类和II类，以及细胞谱系标志物。Gp 120诱导的细胞因子，特别是IFN-γ，上调细胞间粘附分子如ICAM-1的细胞表达。我们已经表明，IFN-γ驱动的ICAM-1表达的增加由慢性感染HIV-1的细胞可以传递到病毒后代，导致病毒的表型改变，并导致其宿主细胞谱扩展到表达适当配体，即LFA-1的CD 4阴性细胞。细胞间粘附分子也参与HIV感染的细胞介导的传播，IFN-γ诱导的ICAM-1表达增加决定了HIV从流产感染的内皮细胞向允许的CD 4淋巴细胞传播的刺激。总的来说，这些数据表明，HIV或其可溶性产物如gp 120，可以通过诱导许多细胞因子和免疫激活的部分状态来改变几种PBMC功能。gp 120驱动的PBMC功能变化可能不仅是HIV感染的附带现象，而且可能参与导致疾病进展的免疫病理学事件。
Dysfunction of cytokine secretion pattern has been suggested to play a central role in the immunopathogenesis of HIV infection. In fact a shift of T helper cell functions from a Th1-type to TH0- or TH2-type has been observed in HIV-1 infected subjects undergoing disease progression. The inhalance of cytokine network is accompanied by persistent activation of the immune system, impaired ability to mount a proper activation response (anergy), and priming to apoptosis. Extensive investigation during the last decade has been conducted on the influence of HIV-1 gp120 or of its precursor gp160 on several lymphocyte and monocyte functions. Gp120 is able to rise intracellular calcium concentration and to induce the formation of inositol triphosphate, can block mitogen- or antigen-driven T cell activation, can induce altered cytokine production by activated PBMC subpopulations, determines impaired cytotoxicity and chemotactic response to antigens, interferes with the activity of antigen presenting cells, enhances or induces apoptosis, stimulates polyclonal B cell activation and induces or up-modulates a number of cytokines, including IL-6. TNF, IL-1-alpha and -beta, IL-10 and IL-8. Furthermore, both IFN-alpha and -gamma, as well as several markers of IFN activity, such as beta 2-microglobulin and neopterin, are induced in gp120-stimulated PBMC. However, neither IL-4 (Th2-type) nor IL-2 (Th1-type), nor DNA synthesis are activated by gp120. On the other hand gp120-stimulated PBMC express increased IL-2 receptors, and can be induced by exogenous IL-2 to proliferate, suggesting that they are in a state of at least partial activation. According to this hypothesis, other activation markers, both early (such as CD69), and late (such as CD45RO and CD71), are induced by gp120, but this even partial activation does not lead to the ability of PBMC to support productive infection by HIV-1, unless in the presence of exogenous IL-2. The HIV-induced cytokines can influence HIV infection either directly, by up- or down-modulating virus replication, or indirectly, by modulating the expression of cellular molecules. In fact, during the budding process, the HIV envelope captures a number of cell membrane proteins, including cytokine receptors such as IL-2R, adhesion molecules such as LFA-1, ICAM-1, -2, HLA Class I and II, as well as cell lineage markers. Gp120-induced cytokines, particularly IFN-gamma, upmodulate the cellular expression of intercellular adhesion molecules, such as ICAM-1. We have shown that the IFN-gamma-driven increase of the expression of ICAM-1 by cells chronically infected with HIV-1 can be transmitted to the virus progeny, resulting in phenotypic alteration of the virus, and leading to the expansion of its host cell spectrum to CD4-negative cells expressing the appropriate ligands, i.e. LFA-1. Intercellular adhesion molecules are also involved in the cell-mediated transmission of HIV infection, and the increased ICAM-1 expression induced by IFN-gamma determines a stimulation of the transmission of HIV from abortively infected endothelial cells to permissive CD4 lymphocytes. On the whole, these data indicate that HIV, or its soluble products such as gp120, can modify several PBMC functions, by inducing a number of cytokines and a partial state of immune activation. It is possible that the gp120-driven changes of PBMC functions are not only an epiphenomenon of HIV infection, but rather, it is likely that they can participate in the immunopathological events responsible for disease progression.