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: 10203816
• 负责人: David T Evans
• 金额: $ 45.58万
• 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/10203816
• 关键词: AIDS prevention; Address; Affect; Alanine; Amino Acid Sequence; Amino Acids; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antibody Response; Antibody Therapy; Antiviral Agents; Binding; Biological Assay; 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; 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.

项目摘要 Tetherin，也称为BST-2或CD317，是干扰素诱导的跨膜蛋白，它抑制 从感染细胞中脱离包膜病毒。在干扰素诱导的条件下，Tetherin是 在病毒感染的细胞上上调，并在试图从细胞表面芽芽时捕获新生的病毒体。 而大多数猿猴免疫缺陷病毒（SIV）都使用NEF反对其蛋白 非人类灵长类动物宿主，HIV-1 VPU和HIV-2 Env已经获得了抵抗人Tetherin的能力 由于在人的系带中没有五个氨基酸序列，因此对NEF的敏感性感到敏感。我们 以前证明，VPU的Tetherin拮抗作用可保护感染HIV的细胞免受抗体依赖性 细胞细胞毒性（ADCC）。现在，我们表明VPU的抗螺旋活性也保护感染了HIV的细胞 来自抗体依赖性细胞吞噬作用（ADCP）。这些发现表明，通过将病毒体捕获在 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的抗病毒活性在体内可能比以前所欣赏的要大得多。当前的建议 以这些研究为基础，以解决Tetherin作为先天和与世隔绝的总体假设 适应性免疫以增强病毒感染细胞对抗体的敏感性。 在AIM 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多大程度的因素 Tetherin可以促进ADCP，这将更好地了解如何使用这些互动 改善基于抗体的HIV-1感染治疗方法。在AIM 2中，我们将利用SIV的力量 感染恒河猴作为动物模型，以评估病毒对策对 Tetherin和Serinc5到慢病毒复制和发病机理。这些研究将揭示Tetherin的影响 和Serinc5在慢病毒感染和可能源自抗逆转录病毒药物的治疗益处 旨在提高HIV-1对这些限制因素的敏感性。在AIM 3中，我们将检验假设 该系带增强了抗体介导的对SIV感染猕猴中病毒复制的控制。这些研究 对于我们对Tetherin和抗体之间的协同作用的基本理解至关重要 利用这些相互作用来治疗和预防HIV-1感染。