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治疗（HAART），但HIV相关感觉神经病变（HIV-SN）的发生率仍然很高。虽然HIV及其炎症反应以及抗逆转录病毒治疗的毒性作用被认为是重要的致病因素，但这两个因素如何影响启动HAART的个体中HIV-SN的致病机制;司他夫定（d4 T），一种神经性抗逆转录病毒（ARV）药物，如何改变发病机制和相互作用;即使短期使用d4 T是否会对神经造成不可修复的损伤也没有很好的定义。d4 T诱导的神经病变问题在d4 T大量使用的发展中国家尤其令人担忧。我们的计划，通过我们的合作协调中心，（东南亚研究合作与夏威夷），打算推出一个150 N，72周，临床试验（2003）评估短期d4 T+拉米夫定[3 TC]（24周）随后齐多夫定[ZDV] +3 TC（n= 50）与连续ZDV +3 TC（n = 50）或替诺福韦（TDF）+恩曲他滨（FTC）（n=50），均与奈韦拉平（NVP）联合用于泰国曼谷的ARV初治受试者。在本试验的框架内，我们建议评估HAART对表皮神经纤维密度（ENFD）的系列（基线，第24周和第72周）测量值的影响，ENFD可能是HIV-SN的病理相关性。我们将评估ENFD的改善是否通常与HAART诱导的免疫病毒学参数的预期改善一起发生，这是如何通过使用d4 T改变的，以及ENFD的低基线或差异变化是否预测HAART启动个体的HIV-SN的发展。为了评估其发展中涉及的发病机制，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，氧化磷酸化复合物I和IV，mt特异性8-氧代脱氧鸟嘌呤）以及细胞内d4 T三磷酸水平的关系。我们还将评估其与PBMC的CD 14+亚组分内HIV DNA水平的关系，我们假设PBMC代表HIV感染的M/M7，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HIV-SN如何发展的理解，并可能导致有效的预防/治疗方式。公共卫生相关性本提案将研究低基线外周神经纤维密度（负责四肢疼痛的神经）是否可预测神经病变（四肢疼痛）的发生，以及接受抗逆转录病毒治疗的HIV感染受试者是否会对其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HIV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.