大腦中的愛滋病毒——它與神經認知症狀有關嗎？
Zekerie Redzheb / 2023 年 10 月 18 日 / aidsmap
多米齊亞·薩盧斯特 | www.domiziasalusest.com
在某些情況下，愛滋病毒可以繞過包圍大腦和腦脊髓液的屏障，從而導致大腦發炎和神經認知症狀。 然而，由於其解剖學上的難以接近，診斷這種病毒「逃脫」到腦脊髓液的情況具有挑戰性。 瑞士研究人員發現，病毒的存在與症狀並沒有明顯的相關性。 在《後天免疫缺乏症候群期刊》上發表的論文中，他們也得出結論，了解病毒是否存在於腦脊髓液中的唯一方法是直接從脊椎中抽取少量液體。
大腦、脊髓和周圍的液體透過所謂的血腦屏障與身體的其他部分分開。 它的主要功能之一是保護脆弱的神經系統免受身體其他部位可能發生的感染。 周圍的液體稱為腦脊髓液（CSF），其含量可能會根據大腦的健康狀況和血腦屏障的完整性而變化。 在一些愛滋病毒感染者中，即使在血液中檢測不到病毒，病毒也可能進入腦脊髓液或大腦。
有幾個因素會影響愛滋病毒是否會到達大腦以及是否會導致神經認知缺陷。 其中一些是人類所擁有的病毒株的神經毒力（它對神經細胞的吸引力）； 包圍大腦、脊髓及其液體的屏障的健康狀況； 免疫系統的狀態和其他感染的存在。 然而，對於病毒受到抑制的人類腦脊髓液中病毒的存在是否會直接導致症狀和缺陷存在爭議，並且可能因人而異。 此外，在許多情況下，雖然沒有檢測到病毒，但症狀和缺陷仍然存在。
科學家依靠檢測腦脊髓液中的愛滋病毒作為病毒「逃脫」到中樞神經系統（大腦和脊髓）的明確證據。 然而，這是一種侵入性技術，稱為腰椎穿刺或脊椎穿刺。 它涉及使用穿透下脊椎的注射器從腦脊髓液中採集樣本，並伴隨頭痛和腿部短期麻木等風險。 在極少數情況下，它會導致嚴重感染。 腰椎穿刺也可用於檢查某些發炎蛋白，以幫助確定是否有腦部發炎。 本研究著重於接受腰椎穿刺的人的大量資料； 作者未能找到腦脊髓液中病毒的存在與症狀之間的明確聯繫，並確定有和沒有病毒逃脫的患者的臨床特徵是相似的。
研究
研究人員從兩個瑞士愛滋病毒感染者群體中收集了數據，重點關注神經認知和代謝健康。 他們關注了 288 名患有神經認知症狀並在 2011 年至 2019 年間接受過腰椎穿刺的參與者。
除了測試腦脊髓液中的 HIV RNA 外，研究人員還觀察了腦脊髓液的其他特徵，如白血球計數、CD4 計數和蛋白質水平，以大致了解中樞神經系統的發炎狀態。 為了真正做到全面，他們甚至對腦脊髓液中檢測到的病毒進行了抗藥性測試，研究了參與者的藥物組合與他們到達腦脊髓液的能力的關係，最後進行了腦部掃描（MRI）以尋找結構變化在大腦。
25 名參與者出現病毒逃脫
腦脊髓液中的病毒逃脫定義為在接受治療達無法檢測到病毒的患者中腦脊髓液中任何可檢測到的病毒，或在未受到病毒抑制的患者中腦脊髓液病毒量大於血液病毒量。 在 288 名參與者中的 25 名中發現了這種病毒，其中 19 名在腦脊髓液中病毒逃脫時病毒受到抑制（無法檢測到）。
有趣的是，那些有病毒逃脫和沒有病毒逃脫的人在其他參數方面沒有區別，例如診斷後的時間、CD4計數、神經認知評分、其他健康狀況以及其治療方案到達腦脊髓液的有效性。 換句話說，沒有任何東西可以預測病毒的逃脫。
有或沒有病毒逃脫的人的 MRI 結果相似
研究人員進行了腦部掃描（MRI）來尋找大腦的結構變化。 兩組（有或沒有病毒逃脫的組別）均觀察到輕微至中度的大腦變化，涉及不同的大腦區域。 研究發現，每組中近 70% 的參與者的大腦發生了某種結構變化。
神經認知變化率相似
神經認知症狀的存在是基於自我報告的主訴或臨床醫生觀察到的。另一方面， 神經認知障礙（NCI）是透過神經認知測試進行評估。
無論是否有病毒逃逸，無症狀神經認知障礙（每組約 40%）和輕度神經認知障礙（低於 5%）的發生率相似。 有趣的是，在沒有病毒逃脫的組別中觀察到一名患有愛滋病毒相關癡呆的參與者，而在病毒逃脫組中沒有一名參與者，這很有趣，但並不重要。
三名參與者的腦脊髓液抵抗
從三名可偵測到腦脊髓液病毒量的參與者身上分析出的病毒對他們在測量時所採取的治療有抵抗力，而他們血液中的病毒則沒有抵抗力。 這凸顯了中樞神經系統的孤立性，而有些病毒學事件可能在該解剖部位獨立發生。
腰椎穿刺是否合理？
我們對神經認知參與和伴隨愛滋病毒感染良好治療而發生的變化的理解仍處於起步階段。 儘管如此，這項研究還是取得了重大進展，顯示有和沒有病毒腦脊髓液逃脫的患者之間沒有臨床差異。 因此，沒有什麼可預測的。 唯一確定的方法是腰椎穿刺，但是，它合理嗎？ 在有效的愛滋病毒治療背景下，神經認知障礙似乎是多種因素的作用，其中腦脊髓液逃脫只是其中之一。 在這種情況下，腰椎穿刺分析是否有助於改善患者的治療結果和生活品質？
許多專家認為，腰椎穿刺至少可以指導醫療保健從業人員選擇更能到達腦脊髓液的藥物組合； 然而，很少有數據顯示治療優化（或強化）有助於改善已經無法檢測到的病毒逃脫族群的神經認知症狀。 與預期相反，迄今為止的大多數數據似乎都顯示這種方法沒有必要或效果極低； 在某些情況下，由於藥物本身的副作用，增加藥物負擔可能會加重這些症狀。
鑑於病毒逃脫與已接受治療的無法檢測到病毒的患者的神經認知症狀和缺陷之間的相關性相當不令人信服，證明病毒逃脫可能在常規臨床照護中沒有用處。 病毒、免疫系統和中樞神經系統的局部免疫之間存在著複雜的相互作用。 迄今為止的證據似乎顯示這種相互作用，而不僅僅是腦脊髓液中病毒的存在，決定了是否會出現症狀和缺陷。
然而，有一件事是肯定的——愛滋病毒感染者面臨更高的神經心理和神經認知障礙發生率，必須探索所有可能的介入途徑以改善生活品質。 迄今尚未充分探索的一個可能性領域是對中樞神經系統的免疫介入。 當病毒已經無法檢測到時，可以透過各種針對大腦的抗發炎藥物或其他藥物來改善免疫反應，而不是直接關注病毒，使腦脊髓液的免疫環境更有利於大腦健康。
參考文獻：
Filippidis P等人。 有神經認知症狀的患者中 HIV-1於腦脊髓液逃脫：來自 Neuro-HIV 平台和 NAMACO 研究的匯總數據。 JAIDS 《後天免疫缺陷症候群雜誌》 93：219-228，2023 年（開放取用）。DOI：10.1097/QAI.0000000000003189
HIV in the brain – does it correlate with neurocognitive symptoms?
Zekerie Redzheb / 18 October 2023 / aidsmap
Domizia Salusest | www.domiziasalusest.com
In some cases, HIV can bypass the barrier that encases the brain and cerebrospinal fluid which can contribute to brain inflammation and neurocognitive symptoms. However, diagnosing this viral ‘escape’ into cerebrospinal fluid is challenging due to its anatomical inaccessibility. Swiss researchers found that the presence of the virus did not clearly correlate with symptoms. In their paper published in the Journal of Acquired Immunodeficiency Syndromes, they also conclude that the only way to know whether the virus is present in the cerebrospinal fluid is taking a small amount of fluid directly from the spine.
The brain with the spinal cord and the surrounding fluid are separated from the rest of the body by the so-called blood-brain barrier; one of its major functions is to protect the fragile nervous system from infections that may take place elsewhere in the body. The surrounding fluid is called cerebrospinal fluid (CSF), and its content may change depending on the health of the brain and the integrity of the blood-brain barrier. In some people with HIV, the virus may make its way into the cerebrospinal fluid or the brain, even when the virus is undetectable in their blood.
Several factors can affect whether HIV will reach the brain and whether that will lead to neurocognitive deficits. Some of these are the neurovirulence (its attraction to nerve cells) of the strain of the virus a person has; the health of the barrier that encases the brain, the spinal cord and its fluid; the state of the immune system and the presence of other infections. However, whether the presence of the virus in the cerebrospinal fluid in otherwise virally suppressed people directly leads to symptoms and deficits is debated and may vary from person to person. Besides, there are many cases where the virus is not detected but symptoms and deficits persist.
Scientists rely on detecting HIV in CSF as a definitive proof for viral ‘escape’ into the central nervous system (brain and spinal cord). However, this is an invasive technique known as lumbar puncture or spinal tap. It involves taking a sample from the CSF using a syringe that penetrates the lower spine and comes with risks such as headache and short-term numbness in legs. Rarely, it can lead to serious infections. Lumbar puncture can also be used to look at certain inflammatory proteins to help decide whether there is brain inflammation. The present study looks at a large set of data from people who underwent lumbar puncture; the authors failed to find a definitive link between viral presence in CSF and symptoms and established that the clinical features of those with and without viral escape were similar.
The study
The investigators collected their data from two Swiss cohorts of people living with HIV focused on neurocognitive and metabolic health. They focused on 288 participants who had neurocognitive symptoms and had undergone lumbar puncture between 2011 and 2019.
As well as testing the CSF for HIV RNA, the researchers also looked at other features of CSF such as white blood cell count, CD4 count and protein levels to get an approximate idea of the inflammatory state of the central nervous system. In order to really be comprehensive, they even ran resistance tests on the virus when detected in CSF, looked at the drug combinations of participants in relation to their ability to reach the CSF and finally did a brain scan (MRI) to look for structural changes in the brain.
Viral escape in 25 participants
Viral escape in CSF was defined either as any detectable virus in CSF in otherwise undetectable people on treatment, or CSF viral load greater than blood viral load in those who were not virally suppressed. It was found in 25 of the 288 participants, including 19 who were otherwise virally suppressed (undetectable) at the time they had viral escape in CSF.
Interestingly, there was no distinction between those with and without viral escape in terms of other parameters such as time since diagnosis, CD4 count, neurocognitive scores, other health conditions and effectiveness of their regimen in reaching the CSF. In other words, there was nothing predictive of the viral escape.
Similar MRI findings in those with and without viral escape
The investigators did brain scans (MRI) to look for structural changes in the brain. Subtle to moderate brain changes were observed across both groups (those with and without viral escape) with involvement of different brain regions. Nearly 70% of participants in each group were found to have some kind of structural change in their brain.
Similar rates of neurocognitive changes
The presence of neurocognitive symptoms was based either on self-reported complaints or those observed by a clinician. Neurocognitive impairment (NCI), on the other hand, was assessed through neurocognitive tests.
Both, those with and without viral escape had similar rates of non-symptomatic neurocognitive impairment (around 40% in each group) and mild neurocognitive impairment (less than 5%). It was interesting, but not significant, to observe one participant with HIV-associated dementia in the group without viral escape, while there were none in the viral escape group.
CSF resistance in three participants
The virus analysed from three of the participants with detectable CSF viral load was resistant to the treatment they were taking at the time of the measurement, while the virus in their blood had no resistance. This highlights the isolated nature of the central nervous system and that some virological events may take place independently in that anatomical site.
Is lumbar puncture justifiable?
Our understanding of the neurocognitive involvement and changes that accompany well-treated HIV infection is still in its infancy. Nevertheless, this study makes a major stride by showing that there were no clinical differences between those with and without viral CSF escape; hence, there was nothing predictive. The only definitive method is lumbar puncture, however, is it justifiable? In the contex