儘管長期抑制病毒，但有缺陷的 HIV 顆粒仍可能引發炎症
資料來源：Zekerie Redzheb / 2023 年 10 月 6 日 / aidsmap
Kateryna Kon/Shutterstock.com
愛滋病毒感染者會經歷持續的低水平炎症，與普通人群相比，這可能會導致健康狀況惡化，但要確定其確切原因一直具有挑戰性。 美國國家衛生研究院科學家的合作發現，愛滋病毒感染者的持續發炎與有缺陷的愛滋病毒顆粒有關。 他們的工作也證實了病毒成分的存在，儘管其狀態如《愛滋病》雜誌中所描述的那樣無法檢測到。
持續的免疫活化和發炎會導致免疫系統衰竭，並長期損害器官和系統。 整體發炎狀態加劇是心臟病等許多慢性健康狀況的根源。 對於愛滋病毒感染者來說，可能有許多原因可以解釋低度炎症，例如某些愛滋病毒藥物、吸菸和其他生活方式因素或合併感染。 然而，主要的嫌疑始終是病毒本身。 儘管被抑制，人們認為該病毒仍以某種方式持續觸發免疫系統。
有缺陷的病毒可以在我們體內持續產生外來蛋白質，這一事實足以讓免疫系統保持警惕，從而處於持續的發炎狀態。 目前的研究證實，即使經過多年的病毒抑制，缺陷的 HIV 序列和蛋白質的存在仍與一些發炎標記物相關。
這些有缺陷的病毒無法成功繁殖，也無法感染新細胞，但它們似乎在一些受感染的「儲存細胞」中活躍地產生。 在這項研究中，研究人員測量了三種類型的病毒成分：病毒 RNA、DNA 和蛋白質。 病毒RNA是HIV的遺傳物質，攜帶其「製造」的代碼，它要麼自由存在於細胞內，要麼在繼續感染其他細胞時被包裝在病毒的塗層中。 這些蛋白質是形成病毒外殼並幫助其自我複製的成分。 在細胞內，病毒 RNA 轉化為 DNA，DNA 與我們自身的遺傳物質相容，因此它可以嵌入我們的染色體中，從而成為我們細胞不可分割的一部分。
研究
研究人員觀察了一小群愛滋病毒感染者中是否存在這三種病毒成分，其中大多數人正在接受抗病毒治療（ART）並且無法檢測到。 然後，他們試圖追蹤這些病毒成分的數量與 C 反應蛋白 (C-reactive protein)、D-二聚體 (D-dimer)、白細胞介素 6 (interleukin 6)、CD8 細胞計數 (CD8 cell count) 等發炎標記物水平之間的關聯。
二十三位參與者同意為研究提供樣本。 5 名參與者在開始 ART 之前進行了採樣，當時他們已檢測到病毒量，而 15 名參與者在平均接受病毒抑制治療六年時進行了採樣。 另外三位參與者從接受 ART 前開始，每三年定期進行一次抽樣，平均持續 17 年。
病毒成分的水平隨著時間的推移保持不變
儘管缺乏活躍的病毒複製，但在長期定期採樣的三名參與者中，病毒 DNA、RNA（細胞內的病毒）和蛋白質的數量仍然存在且沒有變化，儘管他們的病毒量無法檢測到。 （即使以標準病毒量測試測量，血液中沒有可檢測到的病毒 RNA，細胞內也可能存在 RNA）。
其他參與者的樣本也顯示出類似的結果。 事實上，高達 99.8% 的定序樣本都是有缺陷的病毒。 對此的唯一解釋是病毒的倍增透過受感染的免疫細胞的克隆擴增 (clonal expansion) 並於其中製造有缺陷的病毒成分。克隆擴張是指某些免疫細胞在被某種物質觸發時快速複製自己的能力。 這樣，少量的細胞就可以成長為數百萬個相同的細胞。 如果它們含有愛滋病毒，它們在克隆時會同時增加整合病毒的數量。
透過測量針對病毒蛋白產生的特異性抗體的量來間接測量病毒蛋白的存在。 多年來，所有參與者都保留了愛滋病毒特異性抗體，這支持了這樣的觀點：病毒蛋白即使在無法檢測到的情況下也會持續產生，並不斷觸發免疫系統。
病毒成分的水平與發炎標記物有關
儘管治療後病毒受到抑制，但大多數發炎標記物（例如 C 反應蛋白和白細胞介素 6）的水平幾乎沒有下降。此外，缺陷病毒 RNA 和病毒蛋白的數量之間存在密切聯繫，這顯示缺陷病毒序列可以繼續產生病毒蛋白。 D-二聚體是一種發炎分子，也與有缺陷的病毒 RNA 和病毒蛋白的數量呈正相關。 有趣的是，但並不出乎意料的是，CD8 細胞（負責破壞其他感染細胞的免疫細胞的一個子集）的數量似乎隨著缺陷病毒成分水平的升高而增加。
結論
先前的一項重大研究顯示，有缺陷的病毒可能是可檢測到的病毒載量的原因，這項研究強調了這些有缺陷的病毒顆粒和成分作為導致愛滋病毒感染者發炎加劇的原因的重要性。 由於這些有缺陷的病毒無法複製和產生新病毒，因此很難用藥物來靶向它們。 從某種意義上說，它們已經「死了」，但它們會觸發免疫系統，並可能增加發炎反應並使身體疲憊不堪。 儘管如此，這些發現讓我們更了解，儘管對病毒進行了有效治療，但愛滋病毒感染者出現某些健康問題的頻率卻有所增加。 它們還可以揭示探索和改進愛滋病毒治療的新途徑，這些途徑的重點是免疫系統而不是病毒本身。
參考文獻：
Singh K 等人。 轉錄活性「缺陷」HIV-1 原病毒的長期持續存在：抗反轉錄病毒治療期間持續免疫活化的影響。 《愛滋病》，印刷前線上發表，2023 年 8 月 8 日（開放取用）。
DOI：10.1097/QAD.0000000000003667
Defective HIV particles may drive inflammation despite long-term viral suppression
Zekerie Redzheb / 6 October 2023 / aidsmap
Kateryna Kon/Shutterstock.com
People with HIV experience ongoing low-level inflammation which may contribute to worsened health outcomes compared to the general population, however it has been challenging to pin it down on an exact cause. Findings of a collaboration of scientists from the US National Institutes of Health link the persistent inflammation seen in people with HIV to defective HIV particles. Their work also confirms the presence of the virus’ components despite undetectable status as described in the journal AIDS.
Persistent immune activation and inflammation can lead to the exhaustion of the immune system and damage organs and systems over long stretches of time. A heightened overall inflammatory state is at the root of many chronic health conditions such as heart disease. In people with HIV, there could be many reasons to explain low-level inflammation such as certain HIV drugs, smoking and other lifestyle factors, or co-infections. However, the main suspect has always been the virus itself; despite being suppressed it is thought that the virus somehow keeps triggering the immune system.
The mere fact that defective viruses can keep producing foreign proteins in our body would be enough to keep the immune system alarmed and therefore in a constant inflammatory state. The present study confirms that even after many years of viral suppression the presence of defective HIV sequences and proteins correlates with some inflammatory markers.
These defective viruses cannot multiply successfully, nor can they infect new cells, but they seem to be actively produced in some infected ‘reservoir’ cells. In this study the researchers measured three types of viral components: viral RNA, DNA, and proteins. The viral RNA is the genetic material of HIV that carries the code for its ‘making’ and it exists either freely inside cells or gets packaged in the virus’ coating when going on to infect other cells. The proteins are the components that serve to make the coating of the virus as well as help it copy itself. Inside cells, the viral RNA gets converted into DNA, which is compatible with our own genetic material so that it can lodge itself in our chromosomes – in a way becoming an inextricable part of our cells.
The study
The researchers looked at the presence of the three viral components in a small cohort of people with HIV most of whom were on antiretroviral therapy (ART) and undetectable. Then they tried to trace the link between the amount of these viral components and levels of inflammatory markers such as C-reactive protein, D-dimer, interleukin 6, CD8 cell count and others.
Twenty-three participants agreed to provide samples for the study. Five participants were sampled before they started ART while they had detectable viral loads, while 15 were sampled when they were on treatment with supressed virus for an average of six years. Three additional participants were sampled periodically every three years for an average of 17 years starting from the time before they were on ART.
Levels of viral components remained unchanged over time
Despite the lack of active viral replication, in the three participants who were followed up for a long time with periodical sampling, the amount of viral DNA, RNA (the one inside cells) and proteins remained present and unchanged although they had undetectable viral loads. (Even when there is no detectable viral RNA in blood, as measured in a standard viral load test, there may be RNA inside cells).
Samples from the rest of the participants showed similar results. In fact, up to 99.8% of all sequenced samples were of defective viruses. The only explanation for this is the multiplication of the virus through clonal expansion of the infected immune cells and production of defective viral components in them.
Clonal expansion is the ability of some immune cells to quickly make many copies of themselves when triggered by a certain agent. In this way, a small number of cells can grow into millions of identical cells. If they contain an HIV virus in them, they will simultaneously multiply the number of integrated viruses as they clone.
The presence of viral proteins was measured indirectly by measuring the amount of specific antibodies produced against them. All participants retained HIV-specific antibodies over the years which supports the idea that viral proteins are continually produced even when undetectable and that keeps triggering the immune system.
The level of viral components is linked to inflammatory markers
Despite viral suppression following treatment there was little to no decline in the levels of most inflammatory markers such as C-reactive protein and interleukin 6. Also, there was a strong link between the amount of defective viral RNA and viral proteins which indicates that defective viral sequences can keep producing viral proteins. D-dimer, an inflammatory molecule, also correlated positively to the amount of defective viral RNA and viral proteins. Interestingly, but not unexpectedly, the number of CD8 cells, a subset of immune cells responsible for destroying other infected cells, seemed to increase in response to higher levels of defective viral components.
Conclusion
Coupled with the previous major study that suggested that defective viruses may be responsible for detectable viral load, this study strengthens the importance of these defective viral particles and components as a contributing cause for the heightened inflammation seen in people with HIV. It would be difficult to target these defective viruses with drugs as they are not able to replicate and produce new viruses. In a sense, they are ‘dead’, however they act as a trigger for the immune system and possibly increase inflammatory responses and exhaust the body. Nonetheless, these findings offer us a better understanding of the increased frequency of some health conditions in people with HIV despite effective treatment of the virus. They can also reveal newer avenues for exploration and improvement in HIV treatment that are focused on the immune system rather than the virus itself.
References
Singh K et al. Long-term persistence of transcriptionally-active “defective” HIV-1 proviruses: Implications for persistent immune activation during antiretroviral therapy. AIDS, online ahead of print, August 8 2023, (open access).
DOI: 10.1097/QAD.0000000000003667