Neuroscience and Trauma, Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, United Kingdom; The Albion Centre, The University of Sydney School of Medicine, Sydney, NSW, Australia.
Neuroscience and Trauma, Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, United Kingdom.
Mult Scler Relat Disord. 2018 Aug;24:123-128. doi: 10.1016/j.msard.2018.06.002. Epub 2018 Jun 28.
Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS.
To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS.
This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments.
All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir.
Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.
尽管多发性硬化症（MS）的病因仍不清楚，但很明显，爱泼斯坦-巴尔病毒（EBV）和其他可能的病毒在 MS 的发病机制中起作用。实验室证据表明，人类内源性逆转录病毒（HERVs）也可能起作用，但没有干预疗法可以确定抑制 HERV 会发生什么。最近的流行病学证据表明，HIV 感染患者患 MS 的风险显著降低，HIV 抗逆转录病毒疗法可能巧合地抑制了 HERV 或其他可能与 MS 有关的逆转录元件。
系统研究 HIV 整合酶链转移抑制剂拉替拉韦对活跃复发性 MS 患者钆增强 MRI 病变数量的影响。
这是一项 2a 期临床试验，其中 20 名参与者在基线期进行了 3 个月的入组，随后进行了 3 个月的拉替拉韦 400mg 每日两次治疗。患者每月进行一次钆增强 MRI、唾液采集以检测 EBV 脱落、血液采样进行安全性监测、病毒学（包括 HERVs）、免疫和炎症标志物测量；以及身体、神经和生活质量评估。
所有患者均完成了 6 个月的试验期。MS 疾病活动的主要终点测量指标是观察到的 Gd 增强病变数量，与基线期相比，拉替拉韦在治疗期间对 Gd 增强病变的发展速度没有显著影响。此外，干预措施不能合理归因于残疾或生活质量测量的任何次要终点的变化。在任何就诊时，HERV-W/MSRV（多发性硬化症相关病毒）Gag Flix（荧光指数）B 细胞与 Gd 增强病变数量之间存在显著的正相关（p=0.029），这独立于试验药物给药的任何潜在影响。关于 EBV 脱落，EBV 脱落量与病变数量之间没有显著相关性。干预前后，炎症标志物（IL-8、IL-1β、IL-6、IL-10、TNF、IL-12p70 和 HCRP）均在正常范围内，均未发生变化。拉替拉韦也未改变血清 CD163 的表达。
拉替拉韦对 MS 疾病活动没有任何影响。这可能是由于本研究中使用的抗逆转录病毒药物的选择、治疗 HIV 感染所需的联合药物、治疗期间或剂量方案的短期性、或 HERV 表达在 MS 确立后可能没有作用。EBV 脱落与总病变数量之间的关联具有边缘显著性，可能是由新病变发展驱动的，这可能表明 EBV 脱落作为炎症疾病活动的标志物。总之，我们发现了 HERV-W 标志物、EBV 脱落和新的 MRI 病变之间有趣的相关性，这些相关性独立于治疗效果。
