The role of envelope phosphatidylserine in the binding of HIV to target cells

描述(申请人提供)：HIV感染的第一步是将HIV与其靶细胞结合。对HIV结合的研究使人们对HIV的发病机制以及预防和治疗药物的开发有了进一步的了解。已知HIV与靶细胞的结合是由HIV包膜蛋白gp160介导的。因此，gp160与其受体，包括CD4、趋化因子受体和C型香菇素的相互作用受到了广泛的研究。然而，表达在HIV包膜上的gp160分子的数量很少(14个pg160/病毒粒子的三聚体)，这表明存在一种通过包膜蛋白非依赖的机制来介导HIV结合的机制。事实上，一个研究小组发现，精液中的淀粉样纤维极大地促进了艾滋病毒的复制。我们还发现，血清中的一个因子可以以一种不依赖于包膜蛋白的方式介导伪型HIV载体的结合。该因子将病毒载体与细胞连接起来，使病毒转导能力提高3-30倍。这一途径通常用于吞噬细胞清除死亡细胞。我们已经发现，HIV载体利用凋亡拟态进入靶细胞。在拟议的研究中，我们将调查这种新的病毒结合机制是否涉及艾滋病毒的结合和复制。阐明这一机制将为理解HIV的发病机制和复制开辟新的途径，这将促进新的预防和治疗方法的发展。 公共卫生相关性：尽管已经开发了许多抗艾滋病毒药物，但使用针对艾滋病毒复制的细胞内事件的抗病毒药物，包括逆转录、病毒蛋白的加工、整合和针对病毒包膜蛋白的抗体，用目前的方法从感染患者身上消除艾滋病毒仍然非常困难。在这个提议中，我们将研究一种新的HIV与靶细胞结合的机制，该机制是以不依赖于包膜蛋白的方式介导的。确定这种新的结合机制将导致新的方法，以防止艾滋病毒在人与人之间的传播，并抑制艾滋病毒在患者中的复制。

DESCRIPTION (provided by applicant): The first step of HIV infection is binding of HIV to its target cells. Study of HIV binding has led to an understanding of HIV pathogenesis and development of preventive and therapeutic drugs. It is known that binding of HIV to target cells is mediated by the HIV envelope protein, gp160. Therefore, the interaction of gp160 with its receptors, including CD4, chemokine receptors, and C-type lentins, has been intensively studied. However, the number of gp160 molecules expressed on the HIV envelope is low (14 trimers of pg160/virion), indicating that there is a mechanism mediating HIV binding through an envelope protein-independent mechanism. In fact, one research group found that amyloid fibrils in semen dramatically enhance HIV replication. We also found that a factor in serum can mediate binding of pseudotyped HIV vectors in an envelope-protein independent manner. The factor bridges viral vectors to cells and increases viral transduction 3- to 30-fold. This pathway is typically used for removal of dead cells by phagocytes. We have found that HIV vectors use apoptotic mimicry to enter into target cells. In the proposed studies, we will investigate whether this novel mechanism of viral binding is involved in HIV binding and replication. Elucidation of this mechanism will open new avenues for understanding HIV pathogenesis and replication, which will facilitate development of novel preventive and therapeutic approaches. PUBLIC HEALTH RELEVANCE: Although many anti-HIV drugs have been developed, elimination of HIV from infected patients with current approaches is still very difficult, using anti-viral drugs targeting intracellular events of HIV replication, including reverse transcription, processing of viral proteins, integration, and antibodies against viral envelope proteins. In this proposal, we will study a novel mechanism of HIV binding to target cells, which is mediated in an envelope protein-independent manner. Identification of this novel binding mechanism will lead to new approaches to prevent HIV transmission among people and to inhibit HIV replication in patients.