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

包膜磷脂酰丝氨酸在HIV与靶细胞结合中的作用

• 批准号: 8225125
• 负责人: Koki Morizono
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225125
• 关键词: Amyloid Fibrils; Anti-HIV Agents; Antibodies; Apoptosis; Apoptotic; Baculoviruses; Binding; Bioterrorism; CD209 gene; CD4 Positive T Lymphocytes; Cattle; Cell Line; Cells; Dendritic Cells; Development; Drug Delivery Systems; Engineering; Event; Excision; HIV; HIV Envelope Protein gp160; HIV Infections; HIV Receptors; Homologous Gene; Human; In Vitro; Infection; Investigation; Lassa fever virus; Lead; Mediating; Modeling; Molecular; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phosphatidylserines; Pichinde virus; Preventive; Protein S; Public Health; Research; Reverse Transcription; Role; Ross river virus; Seminal fluid; Serum; Sindbis Virus; TYRO3 gene; Therapeutic; Tissues; Transcription Process; Vaccinia virus; Viral; Viral Envelope Proteins; Viral Pathogenesis; Viral Proteins; Viral Vector; Virion; Virus; Virus Diseases; chemokine receptor; env Gene Products; gp160; in vivo; macrophage; mimicry; novel; novel strategies; prevent; public health relevance; receptor; transduction efficiency; transmission process; vector; virus envelope; vpr Gene Products

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.

描述（由申请人提供）： HIV 感染的第一步是 HIV 与其靶细胞结合。 HIV 结合的研究促进了对 HIV 发病机制的了解以及预防和治疗药物的开发。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lentins）的相互作用得到了深入研究。然而，HIV 包膜上表达的 gp160 分子数量较低（pg160/病毒体有 14 个三聚体），表明存在一种通过包膜蛋白独立机制介导 HIV 结合的机制。事实上，一个研究小组发现精液中的淀粉样原纤维可以显着增强艾滋病毒的复制。我们还发现血清中的一种因子可以以不依赖于包膜蛋白的方式介导假型HIV载体的结合。该因子将病毒载体与细胞连接起来，并将病毒转导能力提高 3 至 30 倍。该途径通常用于吞噬细胞去除死细胞。我们发现HIV载体利用细胞凋亡拟态进入靶细胞。在拟议的研究中，我们将研究这种新的病毒结合机制是否涉及 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：尽管已经开发出许多抗 HIV 药物，但使用目前的方法从感染患者体内消除 HIV 仍然非常困难，因为使用针对 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。在本提案中，我们将研究 HIV 与靶细胞结合的新机制，该机制以不依赖包膜蛋白的方式介导。这种新型结合机制的鉴定将带来预防艾滋病毒在人际传播和抑制艾滋病毒在患者体内复制的新方法。