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

描述（由申请人提供）：HIV感染的第一步是HIV与靶细胞结合。HIV结合的研究有助于了解HIV的发病机制和开发预防和治疗药物。众所周知，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型透镜素）的相互作用已被深入研究。然而，在HIV包膜上表达的gp160分子数量较少（pg160/病毒粒子的三聚体为14个），这表明存在一种不依赖于包膜蛋白的机制介导HIV结合。事实上，一个研究小组发现，精液中的淀粉样原纤维显著地增强了艾滋病病毒的复制。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HIV载体的结合。该因子在病毒载体与细胞之间架起桥梁，使病毒转导增加3- 30倍。该途径通常用于吞噬细胞清除死细胞。我们发现HIV载体利用凋亡模拟进入靶细胞。在接下来的研究中，我们将研究这种新的病毒结合机制是否参与了HIV的结合和复制。这一机制的阐明将为理解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。

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.