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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

基本信息

批准号：
10371090
负责人：
James A Hoxie
金额：
$ 78.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-04-16 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371090
关键词：
Address Amino Acids Anatomy Animal Model Animals Antibodies Antiviral Therapy Binding Biological Assay Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Clonal Expansion Complement Control Animal 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 Macrophage Modeling Mutation Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Predisposition Production Proliferating 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 antibody mimetics antiretroviral therapy cell type decay acceleration experimental study humanized mouse immune activation immunological intervention integration site neutralizing antibody nonhuman primate novel pharmacologic prevent response simian human immunodeficiency virus success synergism trafficking viral RNA viral rebound

项目摘要

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.

项目总结