Oxidant Stress and Antioxidants during HIV Therapy

描述(申请人提供)：有效的抗逆转录病毒疗法(ART)在美国极大地降低了艾滋病毒/艾滋病的发病率和死亡率，并开始在资源有限的环境中产生影响。不幸的是，长期服用抗逆转录病毒药物所产生的毒性已成为一个主要问题。HIV治疗的许多毒性是由于核苷逆转录酶抑制剂(NRTI)的线粒体毒性，NRTI是大多数ART方案的基本成分。尽管氧化应激被认为是线粒体损伤和毒性临床表现之间的基本机制联系，但目前还没有针对大多数ART毒性的特效治疗方法。 这项研究生涯奖的目的是检验这一假设，即由NRTI诱导的线粒体功能障碍导致的氧化应激增加是NRTI毒性途径中的关键步骤：1)建立艾滋病毒感染患者队列，以确认这种氧化应激可以通过测量体内F2-异前列腺素(F2-Isoprostanes，F2-Isop)的产生来可靠地量化；F2-Isops是由自由基催化的花生四烯酸过氧化形成的独特的前列腺素样化合物；2)使用维生素C、E和α-硫辛酸进行一项随机、安慰剂对照的初步研究，以确定哪种抗氧化剂最有效地降低艾滋病毒感染患者的血浆F2-IsoP水平；3)利用试点研究的数据，设计一项大型临床试验，研究抗氧化剂疗法在预防和/或逆转艾滋病毒感染患者氧化应激相关NRTI毒性方面的有效性。 该奖项将提供一名以患者为中心的研究人员的职业发展，研究重点是氧化应激、抗逆转录病毒毒性和抗氧化剂作为艾滋病毒补充疗法的使用。候选人将由两位共同导师指导，一位在艾滋病毒/艾滋病临床研究方面具有专业知识(David Haas博士)，另一位是氧化应激领域的资深研究员和F2-Isop的共同发现者(Jason Morrow博士)。这些共同导师，加上候选人所在机构丰富的研究环境，将确保候选人在艾滋病毒治疗期间在氧化应激和抗氧化剂领域取得重要发现，同时加强其现有的知识基础和研究技能，并获得新的技能。候选人的长期目标是发展成为这一研究领域的独立临床研究员。

DESCRIPTION (provided by applicant): Potent antiretroviral therapy (ART) has dramatically reduced morbidity and mortality due to HIV/AIDS in the United States, and is beginning to have an impact in resource-limited settings. Unfortunately, toxicity due to long-term ART has become a major problem. Many of the toxicities of HIV therapy are due to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI), essential components of most ART regimens. Although it has been suggested that oxidant stress is the fundamental mechanistic link between mitochondrial damage and clinical manifestations of toxicity, there are presently no specific therapies for most ART toxicities. The aims of this Research Career Award are to test the hypothesis that increased oxidant stress resulting from NRTI-induced mitochondrial dysfunction is a critical step in the pathway to NRTI toxicity by: 1) establishing a cohort of HIV-infected patients to confirm that this oxidant stress can be reliably quantified by measuring in vivo production of F2-isoprostanes (F2-IsoPs), unique prostaglandin-like compounds formed by free radical-catalyzed peroxidation of arachidonic acid; 2) performing a randomized, placebo-controlled pilot study using vitamins C, E, and alpha-lipoic acid to identify which antioxidant most effectively reduces plasma F2-IsoP levels in HIV-infected patients; and 3) using data from the pilot study to design a large clinical trial of the efficacy of antioxidant therapy in preventing and/or reversing oxidant stress-associated NRTI toxicities in HIV-infected patients. This award will provide for the career development of an investigator with a patient-oriented research focus in the area of oxidant stress, antiretroviral toxicity, and the use of antioxidants as complementary therapies in HIV. The candidate will be guided by two co-mentors, one with expertise in HIV/AIDS clinical investigation (Dr. David Haas) and the other an accomplished investigator in the field of oxidant stress and co-discoverer of the F2-IsoPs (Dr. Jason Morrow). These co-mentors, together with a rich research environment at the candidate's institution, will ensure that the candidate makes important discoveries in the area of oxidant stress and antioxidants during HIV therapy while strengthening his existing knowledge base and research skills and acquiring new skills. The candidate's long-term goal is to develop into an independent clinical investigator in this field of study.