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Brain myeloid cell-targeted multiplexed gene editing for SIV/HIV eradication

用于根除 SIV/HIV 的脑髓细胞靶向多重基因编辑

基本信息

批准号：
10602472
负责人：
Wenhui Hu
金额：
$ 79.52万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-05 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602472
关键词：
Acute Animals Bar Codes Blood - brain barrier anatomy Blood Vessels Brain Brain region CCL2 gene CCR5 gene CRISPR/Cas technology Capsid Cells Central Nervous System Chinese Chronic Phase Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Cytoprotection DNA Data Early treatment Epidemic Excision Genes Genome Goals Guide RNA HIV HIV Infections HIV-1 HIV/AIDS Immunotherapy In Vitro Individual Infection Injections Intervention Intravenous Latent virus infection phase Libraries Macaca Macaca mulatta Macrophage Measurement Mediating Microglia Modeling Monitor Monkeys Mus Myelogenous Myeloid Cells Names Outcome Plasma Play Prevention Prevention therapy Proviruses Recommendation Regimen Reporter Residual state Role SIV Serotyping Shock Site Source Specificity System Technology Testing Therapeutic Effect Time Tissues Vero Cells Viral reservoir Viremia Virus Virus Diseases antiretroviral therapy blood-brain barrier penetration brain size cell type efficacy evaluation gene therapy genome editing high risk high risk population humanized mouse in vivo mouse model nervous system disorder neural neuroAIDS neurocognitive disorder neuroinflammation nonhuman primate novel novel strategies prevent promoter treatment guidelines viral detection viral rebound

项目摘要

Project Summary The long-lived myeloid cells such as perivascular macrophages and microglia in the central nervous system (CNS) persistently harbor HIV. These infected cells could contribute to the source of residual viremia during long-term antiretroviral therapy (ART) or to rebounding virus upon ART cessation. It is undoubtfully and urgently needed to develop novel strategies to specifically target CNS myeloid cells for HIV eradication and a cure. Be- cause the effects of the widely-studied “Shock and Kill” approach could exacerbate neuroinflammation, gene therapy emerges as the optimal strategy, particularly the advanced CRISPR genome editing technology. Simian immunodeficiency virus (SIV) infection of macaques is the best available model for testing novel strategies prior to clinical studies. We have shown that SIV infection has a broad spread in the CNS even in animals on ART. Because the virus enters the brain within a few days after infection and the establishment of the latent reservoir occurs very early, the initiation of ART should be as early as possible. In addition, numerous studies suggest that CCR5/CCR2 play a major role in HIV entry and neuroinflammation. Most importantly, we have used AAV delivery of a CRISPR/Cas genome editor to eradicate HIV/SIV provirus in models of humanized mice and non- human primates. However, the lack of AAV serotypes that are highly effective and reliable to transduce myeloid cells in the CNS remains a key challenge. Therefore, we hypothesize that the multiple-targeting gene editing system across the blood brain barrier (BBB) can remove SIV provirus in infected myeloid cells, protect cells against new infection, and inhibit neuroinflammation. To test this hypothesis, we will optimize a novel AAV sero- type with BBB penetration and myeloid-specific transduction (namely AAV-BM) to effectively deliver the smaller cjCas9 with multiplex sgRNAs (BMCj4) specific for 4 target sites (SIV LTR, gag, and host CCR5, CCR2) into the entire CNS for in vivo HIV/SIV eradication (Aim 1). We will evaluate the efficacy of BMCj4 early treatment in preventing brain SIV infection or/and excising SIV proviral DNA from brain myeloid cells in acute SIV infection with early ART (Aim 2a). We will also determine the therapeutic effect of BMCj4 with ART and then boost it with an alternative AAV-BM for eradication of persistent brain SIV latent infection (Aim 2b). We expect that early or long-term repeated BMCj4 AAV gene therapy will effectively eradicate acute and latently-infected HIV provirus and extensively minimize the size of the brain viral reservoir to achieve a sterilizing or functional cure of HIV/AIDS, particularly NeuroAIDS.

项目总结