HIV‐lnduced CNS Lesions
HIV‐lnduced CNS Lesions
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HIV 引起的中枢神经系统损伤
DOI：
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发表时间：
1991
期刊：
影响因子：
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通讯作者：
H. Budka
中科院分区：
文献类型：
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作者：
C. Wiley;H. Budka
来自最近的神经科学学会会议。当个别作者准备他们的章节时，一组研究人员被咨询了这个蓬勃发展的领域的术语表。由于共同作者在地理上的分散以及这一领域进展的性质，达成共识是复杂的。正如在任何将一个大主题划分为单独的专题讨论会中所期望的那样，章节之间会出现重叠。虽然其中一些已经被编辑，但在许多情况下，个别作者对其领域边缘的观点提供了对问题的完全不同的观点，因此两种观点都被保留了下来。第一部分由Price博士回顾艾滋病相关神经系统疾病的临床背景。结合过去和推荐的临床术语，Price博士强调临床神经系统综合征不等同于中枢神经系统（CNS）的HIV感染。Budka博士的第二部分回顾了hiv特异性或hiv相关中枢神经系统组织病变的形态学特征，其可能的发病机制和临床相关性。他指出，HIV脑炎和HW脑白质病始终与局部病毒产生增加有关。此外，他认为，第二种致病途径，涉及HIV或其他产物的神经毒性，也得到神经病理学研究的支持。第三部分由dr。Achim， Schrier和Wiley研究了HIV脑炎的免疫发病机制。他们比较了免疫完整个体脊髓灰质炎脑炎的经典中枢神经系统病毒感染和免疫功能低下个体的PML与已知的艾滋病毒脑炎中枢神经系统中发生的免疫反应。在已知这些其他病毒性脑肽的背景下，HIV脑炎的中枢神经系统免疫反应似乎是适当的，然而，缺乏免疫系统的效应侧（特别是CD4阳性辅助细胞）导致中枢神经系统组织内不受控制的HIV感染。为什么中枢神经系统成为HIV感染的储存库可能与免疫细胞和中枢神经系统细胞之间共享的营养细胞因子有关，这些细胞因子导致中枢神经系统巨噬细胞/小胶质细胞内大量的允许性感染。本次研讨会的许多部分涉及“嗜神经性”这一难以捉摸的问题。病毒的嗜神经性包括神经毒性，即引起神经系统疾病的能力；神经侵入性，进入神经系统的能力；以及病毒在适当的中枢神经实质细胞（神经元、星形胶质细胞和少突胶质细胞）内的复制。虽然前两个特性完全适用于艾滋病毒，但第三个特性的证据是有争议的或缺乏的，至少在体内是这样，正如本次研讨会所详尽讨论的那样。认识到这种受限类型的艾滋病毒“嗜神经性”是该病毒最迷人的特性之一，这一点很重要。在病毒-宿主相互关系的背景下，澄清其原因不仅将为我们理解hiv相关的神经系统疾病提供决定性的一步，而且可能对我们理解其他病毒或免疫介导的神经系统疾病有很大贡献。第四部分由dr。Chiodi和Fenyo解决了这个重要问题。154例C.A. Wiley和H. Budka的HIV感染：HIV诱导的中枢神经系统病变是由于免疫控制失败还是出现嗜神经的病毒变体？正如Price博士所指出的那样，虽然罕见的个体会在系统性免疫缺陷之前发展为弥漫性神经疾病，但这显然是规则的例外。然而，艾滋病毒通常可以在感染后很快从中枢神经系统中恢复。许多研究人员试图识别“嗜神经型”艾滋病毒变种。已发现在巨噬细胞和t细胞中生长的双向性菌株，但这些菌株没有选择性中枢神经系统细胞生长。这是我们检测技术的产物还是病毒的真实反映还不清楚。Drs。Chiodi和Fenyo注意到聚合酶链反应可以在各种HIV感染的中枢神经系统细胞系中检测到原病毒，但没有检测到抗原。这种水平的病毒感染是否会对体内中枢神经系统细胞产生生物学效应尚不清楚。Lipton博士的第五部分检查了与HIV感染相关的体外神经毒性。随着研究的展开，一些与HIV感染的巨噬细胞（或受刺激的非感染的巨噬细胞？）相关的因素导致体外神经元死亡。目前尚不清楚什么是神经毒性物质，以及神经毒性的机制是什么。病毒（即gp120）和免疫因子（即细胞因子）都可能在体外造成神经元（和胶质细胞）损伤。随着能够分析这些复杂问题的新方法的发展，钙内流的作用以及所涉及的通道和受体（例如NMDA和非NMDA）才刚刚开始被理解。由于CD4分子在中枢神经系统中的存在是非常有争议的，因此已经提出了啮齿动物和人类神经系统中常见的新的中枢神经系统特异性受体来解释神经营养反应的减弱。这些复杂的问题为hiv相关神经系统疾病的治疗提供了令人兴奋的前景。在第六部分，dr。Lackner， Dandekar和Gardner对HIV脑炎的两种重要动物模型FIV和SIV进行了极好的概述。在这两种动物模型中，免疫抑制和中枢神经系统感染与艾滋病非常相似。病毒在HIV和SIV中的定位实际上是相同的。奇怪的是，FIV的早期报告表明星形胶质细胞也支持生产性感染。如果这一发现得到证实，将为更密切地评估艾滋病毒对中枢神经系统细胞的有限感染增加重要意义。这两种模型都提供了时间尺度和采样能力，以允许研究中枢神经系统疾病在逆转录病毒感染中的发病机制。对神经毒性因素的早期研究与利普顿博士的章节中发现的相似，增强了人们对这些模型的热情。除了六篇专题讨论会文章外，还提供了一份关于艾滋病毒相关神经系统疾病命名法的审查，作为共识报告。作为美国神经病学学会艾滋病特别工作组提出的新临床术语的补充（将与这期《脑病理学》几乎同时在《神经病学》上发表），本文提出了一个基于神经病理学的术语，并对新的实体进行了定义。希望没有看到很多艾滋病病例的神经病理学家能从这些诊断指南中受益。最终目的是让神经病理学家在检查与hiv相关的神经系统疾病时采用一种更通用的语言。Clayton A. Wiley，美国加州大学圣地亚哥分校病理学和神经科学副教授，La Jolla, CA 92093-0612，美国。Herbert Budka，奥地利维也纳A-1090神经病理学大学教授
s from the most recent Society for Neurosciences' meeting. While the individual authors were preparing their chapters, a group of investigators were consulted on a glossary for this blossoming field. Deriving a consensus was complicated by the geographical dispersion of the co-authors, and the nature of progress in this field. As would be expected in any symposium undertaking the division of a large topic into individual parcels, overlap between the chapters occur. While some of this has been edited, in many cases the individual authors' perspective on fringes of their field provides a completely different perspective on the issue and thus both perspectives have been retained. The first section by Dr. Price reviews the clinical background of AIDS related neurologic disease. Jwtaposing both past and recommended clinical terminology, Dr. Price emphasizes the issue that clinical neurologic syndromes are not synonymous with HIV infection of the central nervous system (CNS). The second section by Dr. Budka reviews morphological features of HIV-specific or HIV-associated CNS tissue lesions, their possible pathogenesis, and clinical relevance. He points out that HIV encephalitis and HW leukoencephalopathy are consistently associated with local increase of virus production. In addition, he suggests that a second pathogenic pathway, which involves neurotoxicity of HIV or other products, is also supported by neuropathologic investigation. The third section by Drs. Achim, Schrier and Wiley examines the immunopathogenesis of HIV encephalitis. They compare classical CNS viral infections of polioencephalitis in the immune intact individual and PML in the immunocompromised individual to what is known about the immune response that occurs in the CNS of HIV encephalitis. In the context of what is known about these other viral encephalitides, the CNS immune response in HIV encephalitis appears appropriate, however, absence of the effector side of the immune system (in particular CD4 positive helper cells) results in an uncontrolled HIV infection within CNS tissue. Why the CNS becomes a reservoir of HIV infection may be related to trophic cytokines shared between immune and CNS cells that lead to an abundant permissive infection within CNS macrophages/microglia. Many parts of this symposium deal with the ever elusive issue of 'neurotropism". Neurotropism of a virus encompasses neurovirulence, the ability to cause neurological disease; neuroinvasiveness, the ability to enter the nervous system; and virus replication within the proper CNS parenchymal elements (neurons, astrocytes and oligodendroglia). While the first two properties fully apply to HIV, evidence for the third is controversial or lacking, at least in VIvo, as exhaustively discussed in this symposium. It is important to recognize this restricted type of HIV "neurotropism' as one of the most fascinating properties of the virus. Clarification of its cause, in the context of the virus-host interrelation, will provide not only a decisive step in our understanding of HIVassociated neurological disease, but is likely to contribute greatly to our understanding of other viral or immune-mediated diseases of the nervous system. The fourth section by Drs. Chiodi and Fenyo addresses this important issue. Does HIV infection of the 154 C.A. Wiley and H. Budka: HIV-Induced CNS lesions CNS result from failed immune control or the emergence of a viral variant that is neurotropic? While rare individuals will develop diffuse neurologic disease before systemic immunodeficiency, as pointed out by Dr. Price, this is clearly the exception to the rule. Nevertheless, HIV can frequently be recovered from the CNS soon after infection. Numerous investigators have attempted to identify "neurotropic" variants of HIV. Dual-tropic strains that grow in macrophages and T-cells have been discovered, but these strains show no selective CNS cell growth. Whether this is an artifact of our detection technology or a true reflection of the virus is unclear. Drs. Chiodi and Fenyo note that the polymerase chain reaction can detect provirus in various HIV infected CNS cell lines, but no antigen has been detected. Whether this level of viral infection could have biologic effects on CNS cells in vivo is unknown. The fifth section by Dr. Lipton examines the in vitro neurotoxicity associated with HIV infection. As the story unfolds from studies by a limited number of investigators, some factor associated with HIV infected macrophages (or stimulated non-infected macrophages?) leads to neuronal death in vitro. It is unclear what the neurotoxic agent(s) is and what the mechanism(s) of neurotoxicity is (are). Both viral (i.e., gp120) and immune factors (i.e., cytokines) may account for neuronal (and glial?) damage in vitro. The role of calcium influx and the channels and receptors (e.g., NMDA and non-NMDA) involved are only beginning to be understood as new methodology develops that permit analysis of these complex questions. Because presence in the CNS of the CD4 molecule is highly controversial, new CNS specific receptors common to rodent and human nervous systems have been proposed to account for diminished neurotrophic responses. These complex questions offer an exciting outlook for treatment of HIVassociated neurologic disease. In the sixth section, Drs. Lackner, Dandekar and Gardner provide an excellent overview of two important animal models of HIV encephalitis, FIV and SIV. In both animal models immunosuppression and CNS infection are strikingly similar to that seen in AIDS. Viral localization in HIV and SIV are virtually identical. Curiously, early reports of FIV suggest that astrocytes also support productive infection. If this is confirmed, it would add importance to more closely evaluating limited infection of CNS cells by HIV. Both models offer a time scale and sampling capacity to permit studies of the pathogenesis of CNS disease in retroviral infection. Early studies of neurotoxic factors similar to those identified in Dr. Lipton's chapter heighten enthusiasm about these models. In addition to the six symposium articles, a review of the nomenclature of HIV-associated neurological disease is given as the Consensus Report. As supplementation of new clinical terminology proposed by the American Academy of Neurology AIDS Task Force (to be published by Neurology almost simultaneously with this issue of Brain Pathology), a neuropathology based terminology is proposed here, and the novel entities are defined. It is hoped that neuropathologists who do not see many AIDS cases will benefit from these diagnostic guidelines. The final aim is to have neuropathologists adopt a more universal language when examining HIV-associated diseases of the nervous system. Clayton A. Wiley Associate Professor of Pathology and Neurosciences University of California, San Diego La Jolla, CA 92093-0612, U.S.A. Herbert Budka Professor of Neuropathology University of Vienna A-1090 Wien, Austria