Tethering lentiviral restriction to Fc-mediated antibody responses

将慢病毒限制与 Fc 介导的抗体反应结合起来

• 批准号: 10425358
• 负责人: David T Evans
• 金额: $ 70.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425358
• 关键词: AIDS prevention; Address; Affect; Alanine; Amino Acid Sequence; Amino Acids; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antibody Response; Antibody Therapy; Binding; CD4 Positive T Lymphocytes; Cell Line; Cell surface; Cells; Development; Doxycycline; Drug Design; Engineering; Epitopes; Fc domain; HIV; HIV-1; HIV-2; Human; Immunologics; Infection; Integral Membrane Protein; Interferons; Intravenous infusion procedures; Link; Macaca; Macaca mulatta; Mediating; Mutation; Natural Immunity; Pathogenesis; Phagocytes; Phagocytosis; Positioning Attribute; Predisposition; Proteins; Resistance; SIV; Serine; Specificity; Surface; Testing; Therapeutic; Up-Regulation; Vaccines; Viral; Viral Genome; Viral Load result; Viral Pathogenesis; Virion; Virus; Virus Diseases; Virus Replication; adaptive immunity; antagonist; antibody test; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; combat; experimental study; improved; in vivo; inducible gene expression; insight; macrophage; mutant; nef Genes; nef Protein; neutrophil; nonhuman primate; novel; prevent; receptor; receptor binding; synergism; uptake; virus envelope

PROJECT SUMMARY Tetherin, also known as BST-2 or CD317, is an interferon-inducible transmembrane protein that inhibits the detachment of enveloped viruses from infected cells. Under conditions of interferon-induction, tetherin is upregulated on virus-infected cells and captures nascent virions as they attempt to bud from the cell surface. Whereas most simian immunodeficiency viruses (SIVs) use Nef to oppose the tetherin proteins of their nonhuman primate hosts, HIV-1 Vpu and HIV-2 Env have acquired the ability to counteract human tetherin because of the absence of a five amino acid sequence in human tetherin that confers susceptibility to Nef. We previously demonstrated that tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cellular cytotoxicity (ADCC). We now show that the anti-tetherin activity of Vpu also protects HIV-infected cells from antibody-dependent cellular phagocytosis (ADCP). These findings imply that by trapping virions on the cell surface, tetherin increases the sensitivity of HIV-infected cells to Fc-mediated antibody responses, and that the antiviral activity of tetherin may be much greater in vivo than previously appreciated. The current proposal builds on these studies to address the overarching hypothesis that tetherin serves as link between innate and adaptive immunity to enhance the susceptibility of virus-infected cells to antibodies. In Aim 1, we will determine the immunological mechanisms by which tetherin enhances antibody-mediated phagocytosis of HIV-infected cells. These studies will focus on the factors that influence the extent to which tetherin can promote ADCP, which will provide a better understanding of how to use these interactions to improve antibody-based treatments for HIV-1 infection. In Aim 2, we will take advantage of the power of SIV infection of the rhesus macaque as an animal model to assess the contribution of viral countermeasures to tetherin and SERINC5 to lentiviral replication and pathogenesis. These studies will reveal the impact of tetherin and SERINC5 on lentiviral infection and the therapeutic benefit that may be derived from antiretroviral drugs designed to increase the sensitivity of HIV-1 to these restriction factors. In Aim 3, we will test the hypothesis that tetherin enhances antibody-mediated control of virus replication in SIV-infected macaques. These studies are fundamental to our basic understanding of the synergy between tetherin and antibodies and the potential to exploit these interactions for the treatment and prevention of HIV-1 infection.

项目总结 Tetherin，也被称为BST-2或CD317，是一种干扰素诱导的跨膜蛋白，它抑制 从受感染的细胞中分离被包裹的病毒。在干扰素诱导条件下，Tetherin是 在感染病毒的细胞上表达上调，并在新生病毒粒子试图从细胞表面发芽时捕获它们。 而大多数猴免疫缺陷病毒(SIV)使用Nef来对抗其 非人灵长类宿主HIV-1 VPU和HIV-2 Env已经获得了对抗人类系链的能力 因为人类Tetherin中没有五个氨基酸序列，这使人对Nef易感。我们 先前证明VPU的Tetherin拮抗作用保护HIV感染细胞免受抗体依赖 细胞毒性(ADCC)。我们现在表明，VPU的抗栓蛋白活性也保护了艾滋病毒感染的细胞。 来自抗体依赖的细胞吞噬作用(ADCP)。这些发现表明，通过将病毒粒子捕获在 在细胞表面，Tetherin增加了HIV感染细胞对Fc介导的抗体反应的敏感性，并且 Tetherin在体内的抗病毒活性可能比之前所认识的要强得多。目前的提案 建立在这些研究的基础上，以解决最重要的假设，即Tetherin在先天和 适应性免疫，以增强病毒感染细胞对抗体的敏感性。 在目标1中，我们将确定Tetherin增强抗体介导的免疫学机制。 HIV感染细胞的吞噬作用。这些研究将集中于影响以下因素的程度 Tetherin可以促进ADCP，这将提供对如何使用这些交互作用的更好理解 改进HIV-1感染的基于抗体的治疗。在目标2中，我们将利用SIV的力量 以恒河猴感染为动物模型评估病毒对策的贡献 Tetherin和SERINC5与慢病毒复制和发病机制的关系。这些研究将揭示系留的影响 和SERINC5对慢病毒感染的作用以及抗逆转录病毒药物可能产生的治疗益处 旨在提高HIV-1对这些限制因素的敏感性。在目标3中，我们将检验假设 这种Tetherin增强了抗体介导的对SIV感染猕猴病毒复制的控制。这些研究 对于我们基本理解Tetherin和抗体之间的协同作用以及潜在的 利用这些相互作用来治疗和预防艾滋病毒-1感染。