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.

项目概要 Tetherin，也称为 BST-2 或 CD317，是一种干扰素诱导型跨膜蛋白，可抑制 有包膜病毒从受感染的细胞中分离。在干扰素诱导的条件下，tetherin 在病毒感染的细胞上上调，并在新生病毒粒子试图从细胞表面出芽时捕获它们。 而大多数猿猴免疫缺陷病毒 (SIV) 使用 Nef 来对抗其病毒的系链蛋白 非人类灵长类宿主，HIV-1 Vpu 和 HIV-2 Env 已获得对抗人类 Tetherin 的能力 因为人系链蛋白中缺乏 5 个氨基酸序列，而这赋予了 Nef 易感性。我们 先前证明 Vpu 的 Tetherin 拮抗作用可保护 HIV 感染细胞免受抗体依赖性 细胞毒性（ADCC）。我们现在证明 Vpu 的抗系链蛋白活性也可以保护 HIV 感染的细胞 来自抗体依赖性细胞吞噬作用（ADCP）。这些发现意味着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 的体内抗病毒活性可能比之前认识的要强得多。目前的提案 在这些研究的基础上，我们提出了一个总体假设，即系链蛋白是先天和先天之间的纽带。 适应性免疫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。这些研究将重点关注影响程度的因素 tetherin 可以促进 ADCP，这将有助于更好地理解如何利用这些相互作用来 改善基于抗体的 HIV-1 感染治疗。在目标 2 中，我们将利用 SIV 的力量 以恒河猴感染作为动物模型，评估病毒对策对 tetherin 和 SERINC5 对慢病毒复制和发病机制的影响。这些研究将揭示 Tetherin 的影响 和 SERINC5 对慢病毒感染的影响以及抗逆转录病毒药物可能带来的治疗益处 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 Tetherin 增强了感染 SIV 的猕猴中抗体介导的病毒复制控制。这些研究 对于我们对 Tetherin 和抗体之间的协同作用以及潜力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。