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.

项目摘要 Tetherin，也称为BST-2或CD 317，是一种干扰素诱导的跨膜蛋白，其抑制肿瘤细胞增殖。 有包膜的病毒从受感染的细胞上脱落。在干扰素诱导的条件下， 在病毒感染的细胞上上调，并在新生病毒体试图从细胞表面出芽时捕获它们。 尽管大多数猿免疫缺陷病毒（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拴系蛋白的能力 这是因为在人类系链蛋白中缺乏赋予Nef易感性的五个氨基酸序列。我们 先前证明Vpu对系链蛋白的拮抗作用可保护HIV感染细胞免受抗体依赖性 细胞毒性（ADCC）。我们现在发现Vpu的抗栓蛋白活性也能保护HIV感染的细胞 抗体依赖性细胞吞噬作用（ADCP）。这些发现意味着，通过将病毒粒子捕获在 细胞表面，系链蛋白增加HIV感染细胞对Fc介导的抗体应答的敏感性， 栓系蛋白的抗病毒活性在体内可能比以前认识到的要大得多。现时的建议 在这些研究的基础上，我们提出了一个总体假设，即拴系蛋白是先天性和 适应性免疫，以增强病毒感染细胞对抗体的敏感性。 在目的1中，我们将确定系链蛋白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在影响因素的程度， tetherin可以促进ADCP，这将使人们更好地了解如何使用这些相互作用， 改进基于抗体的HIV-1感染治疗。在目标2中，我们将利用SIV的力量 作为动物模型的恒河猴感染，以评估病毒对策对 Tetherin和SERINC 5对慢病毒复制和发病机制的影响。这些研究将揭示拴系蛋白的影响 和SERINC 5对慢病毒感染的作用以及可能来自抗逆转录病毒药物的治疗益处 旨在增加HIV-1对这些限制因子的敏感性。在目标3中，我们将检验假设 在SIV感染的猕猴中，系链蛋白增强了抗体介导的病毒复制控制。这些研究 是我们对系链蛋白和抗体之间协同作用的基本理解的基础， 利用这些相互作用来治疗和预防HIV-1感染。