Smith M O, Heyes M P, Lackner A A
California Regional Primate Research Center, University of California, Davis, USA.
Lab Invest. 1995 May;72(5):547-58.
Encephalitis is a common and devastating sequela of HIV infection in humans and of simian immunodeficiency virus (SIV) infection in rhesus macaques. We used the SIV-infected rhesus macaque model to study early intrathecal events in the pathogenesis of lentiviral encephalitis.
To examine early events and to compare the neuroinvasiveness and neurovirulence of pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of SIV and the role of host immunity in the early postinfection period, we inoculated groups of rhesus macaques with each of these clones and compared them with a third group of animals inoculated with pathogenic uncloned SIV (SIVmac). We collected paired cerebrospinal fluid and sera before and at intervals after inoculation and determined albumin and IgG concentrations, SIV-specific humoral immune response, and concentrations of quinolinic acid. Two animals from each group were killed and necropsied at 2, 8, 13, and 23 weeks after inoculation. Routine histopathology and semi-quantitative in situ hybridization were performed on tissue from multiple levels of the central nervous system (CNS).
SIVmac and SIVmac-239 invaded both the meninges and the CNS parenchyma simultaneously within 2 weeks of inoculation, whereas nonpathogenic SIVmac-1A11 was not neuroinvasive. Gross disruption of the blood-brain barrier was not detected at any time. However, elevated IgG indices and high levels of cerebrospinal fluid quinolinic acid denoted intrathecal immune activation soon after viral neuroinvasion. Virus load in the CNS declined as the immune response peaked but subsequently increased with waning immunity. One macaque that never developed an SIV-specific immune response died with severe SIV encephalitis.
Our findings support the following hypotheses of early events in SIV neuropathogenesis: (a) Pathogenic virus invades the CNS within days of i.v. inoculation and elicits an intrathecal immune response, including intrathecal synthesis of IgG and macrophage activation; (b) the immune response initially is associated with a decreased virus load in the CNS; (c) as immunodeficiency develops, virus load in the CNS increases once again; and (d) both virus and host factors are important in determining the course of events.
脑炎是人类感染HIV及恒河猴感染猿猴免疫缺陷病毒（SIV）后常见且严重的后遗症。我们利用感染SIV的恒河猴模型来研究慢病毒脑炎发病机制中的早期鞘内事件。
为了研究早期事件，并比较致病性（SIVmac239）和非致病性（SIVmac1A11）SIV分子克隆的神经侵袭性和神经毒力，以及宿主免疫在感染后早期的作用，我们用这些克隆分别接种恒河猴组，并将它们与接种致病性未克隆SIV（SIVmac）的第三组动物进行比较。在接种前及接种后的不同时间间隔收集配对的脑脊液和血清，测定白蛋白和IgG浓度、SIV特异性体液免疫反应以及喹啉酸浓度。每组在接种后2、8、13和23周处死两只动物并进行尸检。对中枢神经系统（CNS）多个层面的组织进行常规组织病理学和半定量原位杂交。
SIVmac和SIVmac - 239在接种后2周内同时侵袭脑膜和CNS实质，而非致病性SIVmac - 1A11没有神经侵袭性。在任何时候均未检测到血脑屏障的严重破坏。然而，IgG指数升高和脑脊液喹啉酸水平升高表明病毒神经侵袭后不久鞘内免疫激活。CNS中的病毒载量随着免疫反应达到峰值而下降，但随后随着免疫力减弱而增加。一只从未产生SIV特异性免疫反应的猕猴死于严重的SIV脑炎。
我们的研究结果支持以下关于SIV神经发病机制早期事件的假设：（a）致病性病毒在静脉接种后数天内侵入CNS并引发鞘内免疫反应，包括鞘内IgG合成和巨噬细胞激活；（b）免疫反应最初与CNS中病毒载量降低有关；（c）随着免疫缺陷的发展，CNS中的病毒载量再次增加；（d）病毒和宿主因素在决定事件进程中都很重要。
