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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

基本信息

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
项目类别：
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

项目摘要

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