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Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound

确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献

基本信息

批准号：
10460575
负责人：
JACOB D ESTES
金额：
$ 78.67万
依托单位：
EMORY UNIVERSITY
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：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10460575
关键词：
Achievement Acquired Immunodeficiency Syndrome Address Adherence Age Anatomy Autopsy Biological Markers Blood Brain CCR5 gene CD4 Positive T Lymphocytes CXCR4 gene Cell physiology Cells Clinical Trials Collection Controlled Study Cues DNA Data Development Disease Progression Disease remission Enrollment Equilibrium Fingerprint Genetic Fingerprintings Goals HIV HIV Infections In Vitro Individual Infection Inflammation Interruption Intervention Kinetics Location Longevity Macaca mulatta Mediating Modeling Nature Neuraxis Neuropathogenesis Persons Phagocytosis Primates Recording of previous events Regimen Research Research Personnel Residual state Resistance Rest Role SIV Specimen T-Cell Depletion Time Tissues Variant Viral Viral Genome Viral Load result Viral reservoir Virion Virus Virus Latency Virus Replication Work animal resource antiretroviral therapy brain tissue clinically relevant cost design detection limit in vivo insight macrophage memory CD4 T lymphocyte multidisciplinary novel novel strategies novel therapeutic intervention peer side effect social stigma success synergism viral DNA viral RNA viral rebound

项目摘要

Abstract Despite its success at suppressing viral loads, antiretroviral therapy (ART) cannot eradicate HIV infection. The main obstacle to curing HIV infection is the ability of the virus to persist under suppressive ART in reservoirs of latently infected cells, which are established early after infection and supports rebound to pre-treatment levels if ART is interrupted. Despite the extraordinary challenge of persistent virus reservoirs, a few cases have recently proved that prolonged viral remission after analytical therapy interruption (ATI) is possible. Unfortunately, the specific mechanisms regulating HIV rebound remain very poorly understood, thus critically limiting the development of novel therapeutic strategies aimed at eradication or remission of HIV infection. In this project, we have assembled a multidisciplinary team of investigators to address directly in vivo how the size and relative distribution of the reservoir in CD4 T cells and macrophages govern (i) the anatomic location of persistent viral reservoirs; (ii) the exent of residual inflammation and neuropathogenesis; and (iii) the time and extent of viral rebound after ATI. Specifically, we propose to alter directly in vivo and in a highly relevant model for HIV infection (i.e., the SIV infection of rhesus macaques; RMs) the overall size of virus reservoirs and its distribution between CD4 T cells and macrophages. These goals will be achieved (i) by using the well-established model of ART-treated, SIV-infected RMs; (ii) by using a SIV swarm that allows tracking of multiple viral variants; and (iii) by performing in vivo Ab-mediated CD4 T cell depletion before SIV infection and after SIV-infection during suppressive ART. We will determine how the planned in vivo depleting interventions alter the distribution of viral reservoirs between CD4 T cells and macrophages; impact the kinetics and extent of viral rebound following ATI; and influence the cellular nature and genetic fingerprinting of the rebounding virus. Finally, we will investigate the mechanisms favoring SIV infection and persistence in macrophages when CD4 T cells are depleted. We believe that the complementary, comprehensive, highly synergistic, and rigourosly controlled studies that we propose will provide unprecedented, novel insights into (i) understanding how the cellular nature of the viral reservoir regulate residual inflammation and viral persistence on ART and viral rebound after ATI, and (2) the direct role of macrophages in harboring replication competent virus during long-term ART and contributing to viral rebound after ATI. Critical for our aims, the SIV/RM model allows for investigating the CD4 T cells versus macrophages contribution to viral reservoir not only in blood, but also in a large number of tissues collected longitudinally and at necropsy, including CSF and brain tissues. These achievements will inform efforts to design novel therapeutic strategies aimed at achieving prolonged viral remission of HIV infection.

摘要