Evaluation of the Impact of Spironolactone Use on the Integrity of the XPB-1 Subunit of the TFIIH Complex In Vivo
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- XPB Protein Degradation in CD4+ T Cells
研究概览
简要总结
This is a prospective, interventional, exploratory clinical study designed to evaluate the pharmacokinetics, safety, and biological effects of spironolactone on the degradation of the XPB (ERCC3) protein and its potential impact on the HIV reservoir. Spironolactone is an FDA-approved mineralocorticoid receptor antagonist that has recently been shown in preclinical studies to induce rapid and reversible proteolytic degradation of XPB, a key subunit of the transcription factor IIH (TFIIH) complex, which is essential for cellular transcription, DNA repair, and viral replication.
The study will enroll adult participants, including both HIV-negative individuals and people living with HIV receiving suppressive antiretroviral therapy with undetectable plasma viral load. Participants will receive oral spironolactone with stepwise dose escalation according to individual tolerability, followed by a post-treatment follow-up period.
Primary assessments include evaluation of XPB protein degradation in CD4+ T cells and characterization of the pharmacokinetic profile of spironolactone and its active metabolites. In participants living with HIV, secondary assessments include quantitative and functional measurements of the HIV reservoir. Safety will be monitored throughout the study through clinical evaluations, laboratory testing, and electrocardiographic assessments.
This study aims to generate initial clinical evidence supporting the repositioning of spironolactone as a potential component of HIV cure strategies, particularly within a "block-and-lock" approach targeting sustained viral transcriptional silencing.
详细描述
Detailed Description
This study is an exploratory, interventional clinical investigation designed to characterize the biological and pharmacokinetic effects of spironolactone in adult participants, with a particular focus on its ability to induce proteolytic degradation of the XPB (ERCC3) protein and its potential implications for HIV persistence.
Scientific Rationale
The transcription factor IIH (TFIIH) complex plays a central role in RNA polymerase II-mediated transcription initiation and nucleotide excision repair. XPB (ERCC3), an ATP-dependent 3'-5' DNA helicase and a core subunit of TFIIH, is essential for DNA unwinding during transcription and is also required for efficient replication of several viruses, including HIV. Preclinical studies have demonstrated that spironolactone and its active metabolites induce rapid, reversible proteasomal degradation of XPB without causing generalized cytotoxicity or impairing cellular viability.
In models of HIV infection, depletion of XPB has been shown to inhibit Tat-dependent viral transcription, suppress viral replication, and prevent reactivation of latent proviruses in CD4+ T cells. These findings suggest that pharmacological targeting of XPB may represent a novel host-directed strategy to suppress HIV transcription and stabilize viral latency, consistent with a "block-and-lock" approach to HIV cure research. However, the clinical reproducibility of XPB degradation and its relationship with systemic drug exposure in humans remain insufficiently characterized.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Adults aged 18 to 60 years.
- •Able and willing to provide written informed consent.
- •For HIV-negative cohort: documented HIV-negative test result at screening.
- •For HIV-positive cohort:
- •documented HIV-1 infection;
- •on stable antiretroviral therapy (ART); .plasma HIV-1 RNA below the limit of detection at screening.
排除标准
- •Pregnancy or breastfeeding.
- •Known hypersensitivity or contraindication to spironolactone.
- •Clinically significant baseline electrolyte abnormalities, including hyperkalemia, or conditions that increase the risk of hyperkalemia.
- •Clinically significant renal dysfunction or hepatic dysfunction that, in the investigator's judgment, increases risk with spironolactone.
- •History of clinically significant cardiac arrhythmias or screening electrocardiogram findings that contraindicate spironolactone in the investigator's judgment.
- •Use of aspirin (acetylsalicylic acid) on a continuous basis or recent use prior to screening, or planned use during the study.
- •Current use of medications or supplements that increase potassium levels or otherwise substantially increase the risk of hyperkalemia, or inability/unwillingness to avoid high-potassium supplements and products during the intervention period.
- •Use of non-steroidal anti-inflammatory drugs (NSAIDs) or systemic corticosteroids that cannot be discontinued for the duration of study drug administration.
- •Any condition that, in the investigator's judgment, would interfere with study participation, study procedures, or participant safety.
研究组 & 干预措施
People living with HIV (PLWH)
Participants with HIV on suppressive ART will receive oral spironolactone dose escalation.
干预措施: Spironolactone (drug) (Drug)
People without HIV (HIV-negative)
HIV-negative participants will receive the same oral spironolactone dose escalation.
干预措施: Spironolactone (drug) (Drug)
结局指标
主要结局
XPB Protein Degradation in CD4+ T Cells
时间窗: Baseline through up to 4 weeks of spironolactone treatment.
Change in XPB (ERCC3) protein levels in peripheral blood CD4+ T cells following oral administration of spironolactone, assessed by immunoblotting and expressed as relative protein abundance compared with baseline.
次要结局
- Peak Plasma Concentration (Cmax) of Spironolactone and Canrenone(Baseline to Week 4 of spironolactone treatment.)
- Area Under the Plasma Concentration-Time Curve (AUC) of Spironolactone and Canrenone(Baseline to Week 4 of spironolactone treatment.)
- Elimination Half-Life (t½) of Spironolactone and Canrenone(Baseline to Week 4 of spironolactone treatment.)
- Correlation Between Spironolactone/Canrenone Plasma Concentrations and XPB (ERCC3) Protein Degradation(Baseline to Week 4 of spironolactone treatment.)
- Cell-Associated HIV-1 DNA Levels in CD4+ T Cells(Baseline to Week 4 of spironolactone treatment.)
- Cell-Associated HIV-1 RNA Levels in CD4+ T Cells(Baseline to Week 4 of spironolactone treatment.)
- Replication-Competent HIV Reservoir (QVOA)(Baseline to Week 4 of spironolactone treatment.)
- Safety and Tolerability of Spironolactone(Baseline through study completion (up to 8 weeks).)
研究者
Ferdinando Lima de Menezes
Principal Investigator
University of Sao Paulo General Hospital