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与其靶细胞结合。对HIV结合的研究已经导致了对HIV发病机制的理解以及预防和治疗药物的开发。已知HIV与靶细胞的结合由HIV包膜蛋白gp 160介导。因此，gp 160与其受体（包括CD 4、趋化因子受体和C型lentins）的相互作用已被深入研究。然而，HIV包膜上表达的gp 160分子的数量很低（14个pg 160/病毒体三聚体），表明存在通过包膜蛋白非依赖性机制介导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显著增强了艾滋病毒的复制。我们还发现，血清中的一个因子可以介导假型HIV载体的结合在一个不依赖于蛋白质的方式。该因子将病毒载体连接到细胞，并将病毒转导增加3至30倍。该途径通常用于通过吞噬细胞去除死细胞。我们已经发现HIV载体利用凋亡模拟进入靶细胞。在拟议的研究中，我们将研究这种新的病毒结合机制是否参与HIV结合和复制。阐明这一机制将为理解艾滋病毒的发病机制和复制开辟新的途径，这将有助于开发新的预防和治疗方法。 公共卫生相关性：尽管已经开发了许多抗HIV药物，但是使用当前方法从感染患者中消除HIV仍然非常困难，使用靶向HIV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。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，这种机制是以不依赖于包膜蛋白的方式介导的。这种新的结合机制的鉴定将导致新的方法来防止艾滋病毒在人群中传播，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.