IDENTIFICATION OF CELLULAR RECEPTORS INVOLVED IN HIV INFECTION, TUMOR METASTASIS

HIV-1包膜蛋白的两种成分gp120和gp41被发现能有效抑制人单核细胞上趋化受体的表达和功能，包括趋化因子受体和细菌趋化肽fMLP受体。HIV-1包膜蛋白的抑制作用不是由于与其他趋化剂对受体的直接竞争，而是通过异源脱敏机制，涉及蛋白激酶c的激活。Gp120还抑制趋化因子受体CXCR4在人CD4+ T淋巴细胞中的表达和功能，这需要酪氨酸激酶（p56lck）激活介导的信号事件。我们进一步研究了人类白细胞与HIV-1包膜蛋白肽域的相互作用，这些肽域在HIV-1融合中很重要，发现人类吞噬细胞上的两个7跨膜受体FPR和FPRL1被一些HIV-1包膜域激活。这些受体最初被确定为趋化n -甲酰化肽的激活位点，这些肽要么是合成的，要么是由某些细菌和细胞质线粒体产生的。这些观察结果表明，虽然HIV-1包膜蛋白在介导病毒入侵中至关重要，但它们的结构域也可能引发宿主免疫反应，可能导致宿主先天免疫反应的激活。然而，免疫细胞的强效和长时间激活也可能最终导致细胞对其他刺激物无反应，这是脱敏的结果，这可能有利于艾滋病相关的机会性感染。血清淀粉样蛋白A （SAA）是一种急性期蛋白，通常在0.1 mM水平存在于血清中，但在全身炎症条件下增加1000倍。血清SAA升高的慢性炎症可能最终导致淀粉样变，其特征是组织中淀粉样蛋白原纤维沉积，并伴有器官功能的进行性破坏。我们发现重组人（rh） SAA在体外对人白细胞表现出相当大的化学引诱活性，并诱导小鼠注射部位的这些细胞浸润，这表明SAA在局部存在时可能具有促炎作用。为了鉴定SAA的细胞受体，我们仔细评估了SAA诱导的细胞信号传导模式和其他趋化因子的交叉脱敏。我们发现细菌衍生的趋化肽fMLP在高浓度下能够抑制细胞对SAA后续刺激的反应，这表明SAA可能使用fMLP亲和力较低的白细胞受体。通过对细胞系进行工程改造，使其表达编码多种七跨膜g蛋白偶联受体的基因，我们发现了一种被称为FPRL1的受体，它可以被SAA特异性结合并激活。SAA受体的鉴定将极大地促进SAA在急性期反应和组织淀粉样变中的作用的进一步研究。题目：鉴定HIV-1包膜蛋白中的趋化因子拮抗剂。-急性期反应，癌症，受体，趋化性，HIV-1，

Two components of the HIV-1 envelope protein, gp120 and gp41, were found to potently inhibit the expression and function of chemoattractant receptors on human monocytes, including the receptors for chemokines as well as for bacterial chemotactic peptide fMLP. The inhibitory effects of HIV-1 envelope proteins was not due to a direct competition for the receptors with other chemoattractants, but rather, through a heterologous desensitization mechanism involving the activation of protein kinase C. Gp120 also inhibited the expression and function of chemokine receptor CXCR4 in human CD4+ T lymphocytes, and this required signaling events mediated by tyrosine kinase(p56lck) activation. We further investigated the interaction of human leukocytes with peptide domains in HIV-1 envelope proteins that are important in HIV-1 fusion and found that two 7 transmembrane receptors on human phagocytes, FPR and FPRL1, are activated by some HIV-1 envelope domains. These receptors were originally identified as activation sites for chemotactic N-formylated peptides, either synthetic or produced by certain bacteria and cytoplasmic mitochondria. These observations suggest that while HIV-1 envelope proteins are crucial in mediating viral invasion, their domains may also elicit host immune responses possibly resulting in activation of host innate immune responses. However, a potent and prolonged activation of immune cells may alsoculminate in unresponsiveness of the cells to other stimulants, a consequence of desensitization which could be beneficial for AIDS- related opportunistic infection. Serum amyloid A (SAA), an acute phase protein, is normally present in serum at 0.1 mM levels, but increases by 1000 fold in systemic inflammatory conditions. Chronic inflammatory conditions with elevated serum SAA may culminate in amyloidosis, characterized by deposition of amyloid fibrils in tissues and associated with progressive destruction of organ function. We found that recombinant human (rh) SAA exhibited considerable chemoattractant activity for human leukocytes in vitro and induced infiltration of these cells at injection sites in mice, suggesting that SAA, when present locally, may play a proinflammatory role. In an effort to identify the cell receptor for SAA, we carefully evaluated the pattern of cell signaling induced by SAA and cross-desensitization by other chemotactic factors. We found that the bacterial derived chemotactic peptide fMLP at high concentrations was able to inhibit the cell response to subsequent stimulation with SAA, suggesting that SAA might use a leukocyte receptor for which fMLP has low affinity. By using cell lines engineered to express genes encoding various seven-transmembrane, G-protein coupled receptors, we identified a receptor termed FPRL1 to be specifically bound and activated by SAA. The identification of the receptor used by SAA will greatly facilitate the further research on the role of SAA in acute phase responses and tissue amyloidosis. AIDS TITLE: Identification of chemokine antagonists in HIV-1 envelope proteins. - Acute-phase Response, Cancer, Receptors, chemotaxis, HIV-1,