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Exploration of novel block-and-lock agents alone and in combination for HIV remission in humanized mice

探索新型阻断剂和联合用药在人源化小鼠中缓解 HIV

基本信息

批准号：
10714365
负责人：
J. Victor Garcia-Martinez
金额：
$ 90.32万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-20 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714365
关键词：
Acceleration Aging Aldosterone Antagonists Attention BLT mice Biological Assay Bone Marrow CD4 Positive T Lymphocytes Cancer Patient Cell Line Cells Chronic Clinic Clinical Clinical Research Clinical Trials Cultured Cells DNA Integration Defect Disease Progression Disease remission Dose Drug resistance ERCC3 gene Epigenetic Process Evolution FDA approved Future Gene Expression Genes Genetic Transcription Goals HIV HIV Infections HIV antiretroviral HIV tat Protein HIV-1 Heart failure Hypertension In Vitro Individual Infection Inflammation Integration Host Factors Interruption Length Liver Mineralocorticoid Receptor Modeling Monitor Outcome Pathway interactions Persons Pharmaceutical Preparations Positioning Attribute Provirus Integration Proviruses Residual state Resistance Rest Spironolactone Testing Thymus Gland Time Tissues Transcription Initiation Site Viral Viral Proteins Viral reservoir Viremia Virus antagonist antiretroviral therapy comorbidity cortistatin cost detection limit disease transmission epigenetic silencing experience genetic inhibitor humanized mouse immune activation improved improved outcome in vivo in vivo Model inhibitor insight interest knock-down large scale production memory CD4 T lymphocyte mouse model new therapeutic target novel promoter reactivation from latency small hairpin RNA targeted agent transcription factor transcription factor TFIIH transcriptome sequencing transcriptomics viral RNA viral rebound viral resistance

项目摘要

Abstract HIV-1 transcriptional inhibitors have immense potential in functional cure approaches and could transform the way we treat HIV infections. Unlike current antiretroviral therapy (ART), transcriptional inhibitors offer the prospect of reducing residual viremia derived from reservoir of long-lived cells containing integrated proviruses, likely reducing ongoing the chronic immune activation, inflammation and HIV-associated co-morbidities still experienced by ART-adherent individuals living with HIV. Furthermore, we believe transcriptional inhibitors are amenable to block-and-lock functional cure approaches, aimed at the durable suppression of HIV in the absence of daily therapy, through permanent epigenetic silencing of integrated proviruses. This hypothesis was founded on the activity of the potent Tat inhibitor didehydro-Cortistatin A (dCA). In in vitro and in vivo models of HIV latency, dCA inhibition of HIV transcription over time prompts the viral promoter into deep transcriptional inhibition, limiting viral reactivation upon treatment interruption or with latency reactivating agents (LRAs). Despite their great potential, there are still no HIV transcriptional inhibitors in the clinic, and challenges with the cost of large-scale production of dCA are slowing its progression towards clinical studies. Here we propose to investigate the repurposing the FDA approved aldosterone antagonist Spironolactone (SP) for HIV transcriptional inhibition. An off-target activity of SP is the degradation of the XPB subunit of the general transcription factor TFIIH, a key player in RNAPII initiation at the transcriptional start site (TSS) of genes. We demonstrated in vitro that SP treatment or shRNA knockdown of XPB selectively inhibits HIV transcription and blocks viral reactivation from latency without global transcriptomic defects. This study highlighted the host factor XPB as a novel drug target and SP as a potential block-and-lock agent. Here we propose to explore the potential of SP, alone or in combination with dCA, as a block-and-lock agent in the humanized bone-marrow, thymus liver (BLT) mouse model of HIV infection by: 1) Determine the relationship between SP treatment length with residual viremia levels in tissues and correlates of chronic immune activation/inflammation in HIV infected ART- suppressed BLT mice.; 2) Assess the ability of SP to maintain deep latency as a single drug in the absence of ART and study viral resistance evolution; 3) Impact of dCA and SP in combination as front-line therapy on the size of the established viral reservoir and time to viral rebound. We predict that longer treatment lengths of HIV infected BLT mice with SP will correlate with improved reduction of low-grade HIV persistent transcription from the viral reservoir and likely chronic immune activation. Importantly, we seek to demonstrate that once deep transcriptional suppression is established, SP alone blocks viral rebound. In addition, when used as front-line therapy we expect a reduction in the size of the established viral reservoir and the combination with dCA will improve the outcome. This study will provide an important proof-of-concept for the use of transcriptional inhibitors to treat people living with HIV and explore optimal experimental settings to be tested in future clinical trials

摘要