Targeted interventions to reduce or eliminate the SIV reservoir in a novel model of elite control

有针对性的干预措施，以减少或消除新型精英控制模型中的 SIV 储存库

• 批准号: 10013657
• 负责人: James A Hoxie
• 金额: $ 85.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10013657
• 关键词: Address; Amino Acids; Anatomy; Animal Model; Animals; Antibodies; Antiviral Agents; Antiviral Therapy; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clonal Expansion; Complement; Cytoplasmic Tail; DNA; Future; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Human; Immune; Immune response; Immunologics; Individual; Infection; Intervention; Length; Longevity; Lymphoid; Lymphoid Tissue; Macaca; Modeling; Mutation; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Plasma; Production; Proviruses; Research; SIV; Signal Transduction; Site; T-Lymphocyte; Technology; Testing; Time; Tissues; Viral; Viral Genome; Viral reservoir; Viremia; Virus; Virus Integration; Virus Latency; acute infection; antibody engineering; antiretroviral therapy; base; cell type; experimental study; humanized mouse; immune activation; immunological intervention; integration site; macrophage; neutralizing antibody; nonhuman primate; novel; prevent; response; simian human immunodeficiency virus; success; trafficking; viral RNA; viral rebound; virology

Project Summary HIV-1 infection is typically well controlled with combination antiretroviral therapy (ART). However, viral reservoirs persist in lymphoid tissues leading to rapid rebound viremia following ART discontinuation. The mechanisms that underlie viral persistence include latency, proliferation or clonal outgrowth of cells harboring intact viral genomes, and immune responses that are inadequate to access or kill infected cells. After almost a decade of intensive research to cure HIV infection, there has been little success in eliminating or even reducing HIV-1 reservoirs, indicating that barriers to achieving this goal are formidable. It has become clear that basic questions and mechanisms of how viral persistence is maintained need to be addressed in relevant animal models that can reveal vulnerabilities in these reservoirs and inform hypothesis-driven interventions to impact their size and durability. The Hoxie lab has described a unique nonhuman primate model in which a 2 amino acid deletion in the SIVmac239 envelope cytoplasmic tail, disrupting a highly conserved cellular trafficking signal, produces a virus termed ∆GY that is highly replication fit during acute infection but is rapidly controlled to undetectable levels in plasma by cellular immune responses in the absence of neutralizing antibodies. Viral reservoirs are clearly present years after infection, as demonstrated by anti-CD8 cell depletion studies, and have been detected and quantified by state of the art assays in PBMCs and lymphoid tissue. This proposal will use the ∆GY model of elite cellular control to test the hypothesis that an intervention with a potent and long- lasting neutralizing antibody, with or without the latency reversing-like activity of CD8 cell depletion, thus exerting both cellular and humoral immune attack on the viral reservoir, will accelerate the decay of and/or eliminate replication competent viruses. Four Specific Aims are proposed: 1) to define and quantify viral reservoirs during elite immunologic control of ∆GY, characterizing relevant cell types, transcriptional activity, integration sites, and mechanisms that underlie persistence; 2) determine if long term expression of eCD4-Ig, a novel engineered antibody-like molecule with potent neutralizing and non-neutralizing functions against SIVmac239 and ∆GY, with or without CD8 cell depletion to activate virus production, can synergize with host cellular immune responses to reduce reservoirs; 3) extend findings from Aims 1 and 2 to SIVmac239 infection in which viral control prior to eCD4-Ig and CD8 cell depletion is exerted through ART rather than cellular immune control; and 4) create novel SHIV and HIV-1 isolates that contain mutations analogous to the ∆GY mutation for future studies to explore interventions that can build on the findings of this proposal to reduce or eliminate persisting HIV-1 reservoirs. If viral reservoirs in the ∆GY model can be reduced or eliminated, this study will provide a proof of concept that this goal is feasible, and inform immunological interventions during ART-suppression animal models and in humans.

项目摘要 HIV-1感染通常通过联合抗逆转录病毒疗法（ART）得到良好控制。然而，病毒 储存库持续存在于淋巴组织中，导致ART停止后病毒血症迅速反弹。的 病毒持续存在的基础机制包括潜伏、增殖或携带病毒的细胞的克隆生长。 完整的病毒基因组，以及不足以接近或杀死受感染细胞的免疫反应。经过近一 尽管对治疗艾滋病毒感染进行了十年的深入研究，但在消除甚至减少艾滋病毒感染方面几乎没有取得任何成功。 这表明，实现这一目标的障碍是巨大的。很明显，基本 病毒持续存在的问题和机制需要在相关动物中得到解决， 模型，可以揭示这些水库的脆弱性，并为假设驱动的干预措施提供信息， 尺寸和耐用性。Hoxie实验室描述了一种独特的非人类灵长类动物模型，其中2个氨基 SIVmac 239包膜细胞质尾区的酸性缺失，破坏了高度保守的细胞运输 信号，产生一种名为H5 N戈伊的病毒，该病毒在急性感染期间高度复制，但很快被控制 在不存在中和抗体的情况下，通过细胞免疫应答将其降低至血浆中不可检测的水平。病毒 如抗CD 8细胞耗竭研究所示，感染后数年明显存在储库， 已通过PBMC和淋巴组织中的现有技术测定法进行检测和定量。这项建议会 使用精英细胞控制的神经戈伊模型来检验一个假设，即一种有效的、长期的干预措施， 持久的中和抗体，具有或不具有CD 8细胞耗竭的潜伏期逆转样活性，因此 对病毒储库施加细胞和体液免疫攻击，将加速病毒的衰变和/或 消除可复制病毒。提出了四个具体目标：1）定义和定量病毒 在对大肠杆菌戈伊的精英免疫控制期间的储库，表征相关细胞类型，转录活性， 整合位点和持久性的基础机制; 2）确定eCD 4-IG的长期表达， 具有有效中和和非中和功能的新型工程抗体样分子 SIVmac 239和SIV戈伊，在有或没有CD 8细胞耗竭以激活病毒产生的情况下，可以与宿主协同作用， 细胞免疫应答以减少储库; 3）将目标1和2的发现扩展到SIVmac 239感染 其中在eCD 4-IG和CD 8细胞消耗之前通过ART而不是细胞 免疫控制;和4）产生含有类似于SHIV戈伊的突变的新的SHIV和HIV-1分离物 突变为未来的研究，以探索干预措施，可以建立在这一建议的结果，以减少或 消除持续存在的HIV-1储存库。如果可以减少或消除戈伊模型中的病毒储库， 研究将提供一个概念证明，这一目标是可行的，并告知免疫干预期间， ART抑制动物模型和人类。