Global HIV Drug Therapies and Mitochondrial Complications and Mechanisms

全球艾滋病毒药物治疗和线粒体并发症及机制

基本信息

批准号：
8213520
负责人：
MARIANA GERSCHENSON
金额：
$ 61.34万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213520
关键词：
Accounting Acquired Immunodeficiency Syndrome Address Adipocytes Adipose tissue Adverse effects Affect Anemia Anti-Retroviral Agents Apoptosis Applications Grants Benefits and Risks Biological Assay Body Composition Body fat Bone Marrow Cells Cheek structure Chronic Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Combined Modality Therapy Communicable Diseases Complex Consent DNA-Directed DNA Polymerase Data Developing Countries Development Disease Drug Formulations Enzymes Equilibrium Etiology Evaluation Fasting Fatty acid glycerol esters Funding Generic Drugs Glucose HIV HIV Seropositivity Hawaii Health Hematoxylin and Eosin Staining Method Histologic Human Hypertriglyceridemia Immunohistochemistry In Situ Nick-End Labeling Insulin Insulin Resistance Journals Lamivudine Lead Limb structure Lipids Lipoatrophy Lipodystrophy Literature Liver Measurement Measures Mitochondria Mitochondrial DNA Monitor Nevirapine Nucleosides Oxidative Phosphorylation Oxidative Stress Oxygen Parents Pathogenesis Patients Peripheral Blood Mononuclear Cell Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacotherapy Policies Prevention Principal Investigator Procedures Proteins Protocols documentation Public Health Published Comment Publishing Punch Biopsy Randomized Randomized Clinical Trials Red Cross Regimen Relative (related person)Research Research Personnel Research Subjects Residual state Reverse Transcriptase Inhibitors Risk Safety Serum Skin Skinfold Thickness Specimen Staining method Stains Stavudine Stress Surrogate Markers Swab Tenofovir Thailand Therapeutic Thymidine Time Tissues Toxic effect Triglycerides United States United States Dept. of Health and Human Services Universities Visit Zidovudine analog antiretroviral therapy arm base cardiovascular risk factor cohort design economic value emtricitabine enzyme activity minimally invasive mitochondrial dysfunction nonhuman primate novel open label oxidative damage prevent programs prospective response stem subcutaneous tool treatment duration tripolyphosphate truvada zidovudine triphosphate

项目摘要

DESCRIPTION (provided by applicant): Lipoatrophy and other toxicities due to mitochondrial (mt) dysfunction are common complications seen with the nucleoside reverse transcriptase inhibitors (NRTIs). As hypertriglyceridemia and insulin resistance are also frequently observed in association with lipoatrophy; the use of d4T or ZDV may also increase cardiovascular risk in patients treated with these medications. Despite their toxicities, these NRTIs are widely used components of antiretroviral (ARV) regimens used in developing countries. Even in the United States, ZDV together with lamivudine (3TC) continue to be listed as one of the preferred initial ARV regimens by the Department of Health and Human Services. Therefore, understanding the pathogenic mechanisms underlying the development of these mt toxicities are important to finding appropriate ways to monitor and prevent or minimize the complications of these medications. The University of Hawaii in collaboration with the Thai Red Cross AIDS Research Centre intends to launch a longitudinal 72 week prospective, randomized clinical trial in Bangkok, Thailand assessing the relative toxicities of short-term d4T (24 week) use followed by ZDV (n=50) compared to continuous ZDV + 3TC (n=50) or tenofovir (TDF) + emtricitabine (FTC) (n=50), all given with nevirapine (NVP) in 150 HIV+ na¿ve patients. The clinical trial will be predominantly funded by the Thai Ministry of Public Health as this trial is important to its national ARV treatment policies. We hypothesize that the mt toxicities of these medications are driven primarily by alterations in mitochondrial oxidative phosphorylation (OXPHOS) protein/enzyme activity levels, which in turn increase mitochondrial reactive oxygen stress and adipocytes and pre-adipocyte apoptosis, and that these forces are heavily dependent on the intracellular concentration of these drugs. We further hypothesize that levels of OXPHOS proteins/enzyme activities in fat, peripheral blood mononuclear cells (PBMCs) or buccal cells (cheek swabs) will correlate with a decrease in limb fat content as assessed by dual energy x-ray absorptiometry (DEXA). Should these hypotheses be verified, there would be significant human health relevance in the understanding of the pathogenesis of HIV fat loss. Additionally, PBMCs' or buccal cells' OXPHOS protein/enzyme activities may serve as tools to monitor subjects preemptively for the risk of mitochondrial induced limb fat loss. We intend to evaluate adipose tissue, PBMCs, and buccal cells at baseline, wk 24, and wk 72 for mitochondrial OXPHOS protein/enzyme activity using a novel immunological assay and by immunohistochemistry, mtDNA copies/ cells, mitochondrial specific oxidative damage (8-oxo-deoxyguanine), and apoptosis. Additionally, PBMCs intracellular concentrations of ZDV, d4T, 3TC, FTC, and TDF triphosphates will be assessed for exposure-response relationships with mitochondrial toxicity.

描述（由适用提供）：线粒体（MT）功能障碍引起的脂肪植物和其他毒性是核侧逆转录酶抑制剂（NRTIS）的常见并发症。由于高甘油三酯血症和胰岛素抵抗也经常与脂肪植物相关。使用这些药物治疗的患者的D4T或ZDV的使用也可能增加心血管风险。尽管具有毒性，但这些NRTI是在发展中国家使用的抗逆转录病毒（ARV）方案的广泛使用的组成部分。即使在美国，ZDV与Lamivudine（3TC）一起继续被卫生与公共服务部列为首选的初始ARV方案之一。因此，了解这些MT毒性开发的基础的致病机制对于寻找适当的方法来监测和预防或最大程度地减少这些药物的并发症很重要。夏威夷大学与泰国红十字会艾滋病研究中心合作，打算在泰国曼谷发起纵向72周的前瞻性，随机临床试验，评估短期D4T（24周）使用的相对毒性（24周）使用，然后由ZDV（n = 50）（n = 50），而不是连续的ZDV + 3TC（N = 50）或TENOFIRE（N = 50）或TENOFIRE（FTC）（FTC）（n = 50），全部用奈韦拉平（NVP）给予150名HIV+NA¿VE患者。临床试验将主要由泰国公共卫生部资助，因为该试验对其国家ARV治疗政策很重要。我们假设这些药物的MT毒性是由线粒体氧化磷酸化（OXPHOS）蛋白/酶活性水平的改变而驱动的，这又会增加线粒体的活性氧应激，脂肪细胞和脂肪细胞和辅助细胞的依赖性浓度，并且这些力浓缩了这些药物。我们进一步假设，脂肪，外周血单核细胞（PBMC）或颊细胞（脸颊拭子）中的Oxphos蛋白/酶活性水平与双肢体脂肪含量的降低相关，这些肢体脂肪含量的降低将通过双重能量X射线绝对肽（DEXA）评估。如果这些假设得到验证，则在理解艾滋病毒脂肪损失的发病机理时将具有重要的人类健康相关性。此外，PBMCS或颊细胞的Oxphos蛋白/酶活性可以用作预先监测受试者的工具，以便有线粒体诱导的肢体脂肪损失的风险。 We intend to evaluate adipose tissue, PBMCs, and buccal cells at baseline, wk 24, and wk 72 for mitochondrial OXPHOS protein/enzyme activity using a novel immunological assay and by immunohistochemistry, mtDNA copies/ cells, mitochondrial specific oxidative damage (8-oxo-deoxyguanine), and apoptosis.此外，将评估PBMC的ZDV，D4T，3TC，FTC和TDF三磷酸盐的细胞内浓度，以评估与线粒体毒性的暴露 - 反应关系。