HIV and Global Drug Therapies: Peripheral Neuropathy Complications and Mechanisms

描述(由申请人提供)：尽管引入了高效抗逆转录病毒疗法(HAART)，但艾滋病毒相关感觉神经病(HIV-SN)的发病率仍然很高。虽然艾滋病毒及其炎症反应以及抗逆转录病毒治疗的毒性效应被认为是重要的病因，但这两个因素如何影响发起HAART的艾滋病毒-SN的致病机制；其发病机制和相互作用可能会被一种神经病理性抗逆转录病毒(ARV)药物司他夫定(D4T)改变；以及即使是短期使用d4T也会否发生无法修复的神经损伤。在大量使用d4T的发展中国家，d4T引起的神经病问题尤其令人担忧。我们的计划通过我们的协作协调中心Search(与夏威夷的东南亚研究合作)，打算启动一项为期150 n、72周的临床试验(Search 003)，以评估短期d4T拉米夫定[3TC](24周)和齐多夫定[ZDV]3TC(n=50)与持续服用ZDV 3TC(n=50)或替诺福韦(TDF)恩曲他滨(FTC)(n=50)的相对毒性。在泰国曼谷的ARV-naive受试者中，所有患者都服用奈韦拉平(NVP)。在这项试验的框架内，我们建议评估HAART对一系列(基线、24周和72周)表皮神经纤维密度(ENFD)测量的影响，ENFD可能是HIV-SN的一种病理相关性。我们将评估ENFD的改善是否典型地发生在预期的HAART诱导的免疫病毒学参数的改善中，这种改善是如何通过使用d4T来改变的，以及ENFD的低基线或差异变化是否预测在HAART开始的个体中HIV-SN的发展。为了评估其发病机制，我们将评估神经病变/ENFD与脂肪和PBMC线粒体(Mt)/mt特异性氧化应激参数(mtDNA、氧化磷酸化复合体I和IV，mt特异性8-oxodeoxguanine)以及细胞内d4T三磷酸水平的关系。我们还将评估其与PBMC CD14亚组分中HIV DNA水平的关系，我们假设CD14亚组分代表HIV感染的M/M7细胞，负责周围神经的炎症。最后，我们将评估个体线粒体基因组变异如何影响HIV-SN的发展。这项研究将有助于增加我们对艾滋病毒-SN如何发展的了解，并有可能导致有效的预防/治疗方式。公共卫生相关性这项建议将研究低基线周围神经纤维密度(负责肢体疼痛的神经)是否会预测神经病(肢体疼痛)的发展，以及接受抗逆转录病毒治疗的艾滋病毒感染者是否会对他们的神经纤维密度产生不同的影响。我们还将研究线粒体(细胞的能量来源)和艾滋病毒在神经病变发展中的作用。

DESCRIPTION (provided by applicant): Rates of HIV-associated sensory neuropathies (HIV-SN) remain high despite the introduction of highly active antiretroviral therapy (HAART). While both HIV and its inflammatory responses as well as toxic effects of antiretroviral therapy are believed to be important etiologic factors, how these two factors affect the pathogenic mechanisms underlying HIV-SN in individuals initiating HAART; how the pathogenesis and interactions may be altered by stavudine (d4T), a neuropathic anitretroviral (ARV) medication; and whether irreparable damage to the nerves can occur with even short-term use of d4T is not well defined. The issue of d4T-induced neuropathy is of particular concern in developing countries where d4T is heavily used. Our program, through our collaborative coordinating center SEARCH (South East Asia Research Collaboration with Hawaii), intends to launch a 150 n, 72 week, clinical trial (SEARCH 003) to assess the relative toxicities of short-term d4T + lamivudine [3TC] (24 week) followed by zidovudine [ZDV] + 3TC (n=50) compared to continuous ZDV + 3TC (n=50) or tenofovir (TDF) + emtricitabine (FTC) (n=50), all given with nevirapine (NVP) in ARV-naive subjects in Bangkok, Thailand. Within the framework of this trial, we propose to evaluate the impact of HAART on serial (baseline, week 24 and week 72) measurements of epidermal nerve fiber density (ENFD), a likely pathologic correlate of HIV-SN. We will assess whether improvement in ENFD typically occurs with the expected HAART-induced improvement in immuno-virologic parameters, how this is altered by the use of d4T, and whether low baseline or differential changes in ENFD predict the development of HIV-SN in individuals initiated on HAART. To assess the pathogenesis involved in its development, we will assess the relationship of neuropathy/ENFD to fat and PBMC mitochondrial (mt) /mt-specific oxidative stress parameters (mtDNA, oxidative phosphorylation Complex I and IV, mt-specific 8-oxodeoxyguanine) and to intracellular levels of d4T triphosphates. We will also assess its relationship to levels of HIV DNA within the CD14+ sub-fraction of PBMCs which we hypothesize represent HIV-infected M/M7s responsible for the inflammation surrounding peripheral nerves. Finally, we will assess how individual mitochondrial genomic variations influence the development of HIV-SN. This research will help to increase our understanding of how HIV-SN develops and potentially lead to effective preventive/ therapeutic modalities. PUBLIC HEALTH RELEVANCE This proposal will study whether low baseline peripheral nerve fiber density (the nerves responsible for pain in the extremities) will predict the development of neuropathy (pain in the extremities) and whether HIV-infected subjects on antiretroviral therapy will have different effects on their nerve fiber densities. We will also study the role of mitochondria (a source of energy for the cell) and HIV in the development of neuropathy.