HIV-1病毒與漿細(xì)胞樣樹突狀細(xì)胞的相互作用

彭卓穎，薛 婧，魏 強(qiáng)

(北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，中國醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實(shí)驗(yàn)動物研究所，衛(wèi)生部人類疾病比較醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，國家中醫(yī)藥管理局人類疾病動物模型三級實(shí)驗(yàn)室，新發(fā)再發(fā)傳染病動物模型研究北京市重點(diǎn)實(shí)驗(yàn)室，北京 100021)

HIV-1病毒與漿細(xì)胞樣樹突狀細(xì)胞的相互作用

彭卓穎，薛 婧，魏 強(qiáng)

(北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，中國醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實(shí)驗(yàn)動物研究所，衛(wèi)生部人類疾病比較醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，國家中醫(yī)藥管理局人類疾病動物模型三級實(shí)驗(yàn)室，新發(fā)再發(fā)傳染病動物模型研究北京市重點(diǎn)實(shí)驗(yàn)室，北京 100021)

漿細(xì)胞樣樹突狀細(xì)胞(plamcytoid dendritic cells，pDCs)是一類可以產(chǎn)生大量I型干擾素(interferon α，IFN-α)的固有免疫細(xì)胞。在人類免疫缺陷病毒(human immunodeficiency virus，HIV)急性感染期，pDCs通過分泌IFN-α抑制病毒復(fù)制并激活適應(yīng)性免疫應(yīng)答。在HIV慢性感染期，pDCs通過調(diào)節(jié)免疫細(xì)胞發(fā)揮免疫抑制的作用，不斷破壞淋巴細(xì)胞，從而造成免疫系統(tǒng)崩潰，促進(jìn)疾病進(jìn)程。本文將就HIV-1與pDCs之間的相互作用做一綜述。

漿細(xì)胞樣樹突狀細(xì)胞；人類免疫缺陷病毒；I型干擾素

獲得性免疫缺陷綜合征(acquired immunodeficiency syndrome，AIDS)是人類免疫缺陷病毒(human immunodeficiency virus，HIV)感染機(jī)體后引發(fā)的全身性疾病，其最大特點(diǎn)是破壞適應(yīng)性免疫系統(tǒng)，這也是疾病治療過程中的難點(diǎn)所在。天然免疫系統(tǒng)是機(jī)體抵抗病原體入侵的首要屏障，在病原體感染的早期階段即可對其進(jìn)行控制和清除。樹突狀細(xì)胞(dendritic cells，DCs)是一類特殊的固有免疫細(xì)胞，是HIV-1在粘膜感染途徑中首先接觸到的細(xì)胞，在HIV-1傳播過程中起關(guān)鍵作用[1]。近年來，漿細(xì)胞樣樹突狀細(xì)胞(plamcytoid dendritic cells，pDCs)的功能在艾滋病領(lǐng)域受到廣泛關(guān)注，在HIV-1感染過程中，pDCs可產(chǎn)生大量的IFN-α，IFN-α是重要的免疫調(diào)節(jié)因子，在抗感染和抗腫瘤免疫中發(fā)揮重要作用，對pDCs功能的進(jìn)一步研究可能會給AIDS治療帶來新思路。

1 pDCs的分布及表型特點(diǎn)

pDCs是1958年發(fā)現(xiàn)的一種具有漿細(xì)胞形態(tài)的細(xì)胞[2]，大小介于淋巴細(xì)胞和單核細(xì)胞之間[3]，主要來源于骨髓，可存在于血液循環(huán)中，也可通過趨化因子的作用遷移到淋巴組織(如扁桃體、脾臟、胸腺、粘膜相關(guān)淋巴組織等)及存在炎癥的部位，主要相關(guān)的趨化因子受體為CCR1、CCR5、CXCR3、CXCR4和CCR7[4]。pDCs在外周血單個(gè)核細(xì)胞中所占的比例較小(0.2%～0.8%)，主要表面分子有血液樹突狀細(xì)胞抗原2(BDCA2)、血液樹突狀細(xì)胞抗原4(BDCA4)、IL-3Rα(CD123)、轉(zhuǎn)錄因子E2-2和免疫球蛋白樣轉(zhuǎn)錄本7(ILT-7)，不表達(dá)T細(xì)胞(CD3)、B細(xì)胞(CD19、CD20)和骨髓細(xì)胞(CD13、CD14、CD33)等特有表面分子，所以pDCs的表型為CD4+CD45RA+CD123+CD11c，通過該表型可以將pDCs與骨髓來源的CD11c+DCs細(xì)胞區(qū)分開[5]。

pDCs的內(nèi)體中選擇性高表達(dá)病原模式識別分子TLR7和TLR9，這兩種TLR可通過識別單鏈RNA或富含未甲基化CpG的DNA發(fā)揮作用[6,7]；TLR7直接刺激pDCs分泌IFN-α的能力較弱，但它對pDCs表面分子的影響較大，尤其可以顯著降低BDCA2(CD303)的表達(dá)，BDCA2對IFN-α的產(chǎn)生具有抑制作用[8]；TLR9主要與富含未甲基化CpG的DNA相互作用而發(fā)揮功能，但不同的CpG發(fā)揮的作用也有所不同，如CpG A可通過激活TLR9誘導(dǎo)pDCs大量釋放IFN-α，CpG B可促進(jìn)pDCs的表面共刺激分子(CD80、CD86)及抗原提呈分子(CD83)的表達(dá)[5]。

2 HIV-1感染對pDCs的影響

pDCs被HIV-1感染后釋放出具有感染性的病毒顆粒[9]，并且pDCs可將病毒傳遞給CD4 T細(xì)胞，從而促進(jìn)HIV-1對機(jī)體的感染[10]，但這一過程可被中和抗體阻斷[11]。HIV-1在pDCs內(nèi)的復(fù)制能力較差，這主要與多種宿主限制因子有關(guān)，例如SAMHD1[12]，當(dāng)HIV-1感染pDCs后細(xì)胞內(nèi)SAMHD1的表達(dá)量會有一定程度的降低，但是當(dāng)pDCs與T細(xì)胞共培養(yǎng)時(shí)SAMHD1的表達(dá)量則出現(xiàn)顯著下降，因此增強(qiáng)了HIV-1的復(fù)制，促進(jìn)pDCs成熟及IFN-α的釋放[13]。雖然HIV-1激活pDCs后可釋放大量IFN-α，但是HIV-1不能促使pDCs完全成熟，只是在一定程度上上調(diào)共刺激分子的表達(dá)和炎性細(xì)胞因子的分泌，使得pDCs的抗原提呈作用較弱[14,11]，這可能與HIV-1通過初級內(nèi)體進(jìn)入pDCs有關(guān)，這種感染方式雖然可以介導(dǎo)較強(qiáng)的IFN-α分泌信號，但對pDCs的促成熟作用較弱，且導(dǎo)致NF-κB依賴性的炎性細(xì)胞因子的釋放相對較低[15]。

pDCs暴露于活的或是已滅活的HIV-1都可以釋放大量IFN-α[15]，但是當(dāng)其暴露于包膜有缺陷的HIV-1則無法被刺激產(chǎn)生大量IFN-α，這是因?yàn)镮FN-α的產(chǎn)生有賴于gp160與pDCs表達(dá)的CD4分子相結(jié)合[16,17]。最近研究表明，HIV-1誘導(dǎo)pDCs激活的過程依賴于Env對CD4分子受體的高親和力，而HIV-1的Nef蛋白功能的異?？蓪?dǎo)致CD4分子的下調(diào)，這也可能與病毒膜表面gp160的表達(dá)相關(guān)[18]。

在HIV-1急性感染期，血液循環(huán)中pDCs的數(shù)量會顯著下降[19]，這可能是細(xì)胞被刪除或遷移到淋巴組織的結(jié)果。研究發(fā)現(xiàn)，在HIV-1感染過程中，血液中pDCs的腸道歸巢標(biāo)記分子(α4β7)表達(dá)上調(diào)，隨后pDCs會遷移到腸道粘膜[20,21]，并且發(fā)現(xiàn)pDCs向腸道的遷移與循環(huán)中CD4 T和CD8 T細(xì)胞的Ki67與HLA-DR的表達(dá)上調(diào)有關(guān)，與病毒復(fù)制無關(guān)[22]；pDCs可在此過程中遷移并積累于淋巴結(jié)(lymph nodes，LNs)，通過釋放大量IFN-α調(diào)節(jié)免疫反應(yīng)[23,24]；pDCs還可遷移到脾，但此處的pDCs并不是主要的IFN-α產(chǎn)生細(xì)胞[25]。

3 pDCs所分泌的IFN-α在HIV-1感染中發(fā)揮的作用

目前有多種人源化小鼠模型應(yīng)用于HIV-1感染的研究，如NOD-scid小鼠、NOG小鼠和DKO小鼠等[26，27]，其中人源化DKO小鼠的使用更為普遍，HIV-1感染人源化DKO小鼠后，可有效的感染并激活骨髓和外周淋巴器官中的pDCs[27]，用特異性單克隆抗體BDCA2(CD303)刪除人源化DKO小鼠體內(nèi)的pDCs后，再用HIV-1對小鼠進(jìn)行感染，發(fā)現(xiàn)無法誘導(dǎo)IFN-α的產(chǎn)生和I型干擾素刺激基因(type I interferon-stimulated genes，ISGs)的表達(dá)，并且淋巴器官中T細(xì)胞死亡率降低，HIV-1病毒的復(fù)制明顯增加[28]，這說明pDCs所釋放的IFN-α在HIV-1感染中發(fā)揮重要作用。

3.1 IFN-α與艾滋病發(fā)病密切相關(guān)

猴免疫缺陷病毒(simian immunodeficiency virus，SIV)的天然宿主在急性感染期會快速產(chǎn)生大量IFN-α，但在慢性感染階段這種反應(yīng)出現(xiàn)明顯下調(diào)，從而抑制了疾病進(jìn)展[29]。同樣當(dāng)SIV感染其它致病性宿主時(shí)，無論是疾病長期不進(jìn)展者還是疾病進(jìn)展者，在急性感染期同樣會有大量IFN-α的產(chǎn)生，但在疾病長期不進(jìn)展者的慢性感染期其IFN-α分泌會得到控制，而在疾病進(jìn)展者的慢性感染期其IFN-α依舊持續(xù)性產(chǎn)生，由此表明疾病進(jìn)程與IFN-α的產(chǎn)生相關(guān)，IFN-α的持續(xù)性產(chǎn)生可導(dǎo)致慢性免疫的激活[30,31]，進(jìn)而促進(jìn)CD4 T細(xì)胞消耗并破壞免疫系統(tǒng)，最終發(fā)展為AIDS[32]。還有研究證明，在HIV-1感染過程中不同性別患者的發(fā)病過程有顯著差異，與男性患者相比，女性患者的病毒載量普遍較低，但是疾病進(jìn)程較快，這與女性患者在慢性感染期中較高水平的IFN-α呈正相關(guān)[33]。

3.2 IFN-α的雙重作用

3.2.1 抑制HIV-1的感染及復(fù)制：IFN-α一方面通過促進(jìn)細(xì)胞抗病毒效應(yīng)因子的產(chǎn)生而抑制HIV-1的感染和復(fù)制[34]，另一方面它還可通過誘導(dǎo)靶細(xì)胞內(nèi)具有抗病毒作用的干擾素效應(yīng)基因家族(ISGs)的表達(dá)而增強(qiáng)細(xì)胞抵抗病毒感染的能力[35]。ISGs的上調(diào)既可限制感染細(xì)胞中病毒的復(fù)制，又可使未感染的旁觀者細(xì)胞進(jìn)入抗病毒狀態(tài)，從而降低被感染的風(fēng)險(xiǎn)[36]。而且ISGs中的IP-10可預(yù)測CD4 T細(xì)胞數(shù)量的變化和T細(xì)胞的激活情況，并且與CD4 T細(xì)胞數(shù)量的變化和病毒血癥水平相比，血漿中IP-10的水平更能預(yù)測疾病的進(jìn)展情況[37]，在pDCs的抗病毒過程中起關(guān)鍵作用[38]。

3.2.2 促進(jìn)對免疫系統(tǒng)的破壞：盡管pDCs的抗原提呈能力較弱，但它能通過TLR通路激活抗原提呈作用，產(chǎn)生獲得性免疫反應(yīng)；它也可以通過IDO、ICOSL和PD-L1等激活抗原提呈作用誘導(dǎo)免疫耐受的產(chǎn)生[39]。在不同條件刺激下，pDCs會引起初始輔助性T細(xì)胞的不同極化。Th17主要通過分泌IL-17發(fā)揮維持粘膜屏障功能的完整，該細(xì)胞缺失會引發(fā)細(xì)菌移位和持續(xù)性的炎癥反應(yīng)，促進(jìn)免疫系統(tǒng)的激活[40]；Treg具有抑制其它T細(xì)胞活化的功能，在維持免疫耐受、抑制過度炎癥反應(yīng)和免疫病理方面發(fā)揮重要作用[41]。暴露于HIV-1的pDCs可抑制Th17的產(chǎn)生，但可促使初始CD4 T細(xì)胞向Treg細(xì)胞轉(zhuǎn)化，這個(gè)過程主要依賴于pDCs表達(dá)的吲哚-2,3-雙加氧酶(indolemine 2,3 dioxygenase，IDO)對色氨酸新陳代謝的調(diào)節(jié)作用[40,42,43]。HIV-1感染可促進(jìn)pDCs對IDO的表達(dá)，使TH17與Treg的比率降低，這對HIV-1疾病進(jìn)程中免疫系統(tǒng)的激活有抑制作用。pDCs可以通過對IFN-α的分泌和較弱的抗原提呈能力促進(jìn)免疫系統(tǒng)的激活[42]。在上述兩種作用的平衡過程中機(jī)體進(jìn)入慢性免疫激活狀態(tài)，使得免疫系統(tǒng)持續(xù)性被破壞，機(jī)體對機(jī)會性感染的防御能力降低，進(jìn)而促進(jìn)疾病的進(jìn)展[40]。

IFN-α還可促使靶細(xì)胞釋放趨化因子，并在趨化因子的作用下使靶細(xì)胞向病毒復(fù)制的場所遷移，使得病毒趁機(jī)在機(jī)體內(nèi)建立起系統(tǒng)性感染[44]。在感染過程中，pDCs可通過上調(diào)腫瘤壞死因子相關(guān)凋亡配體(TNF-related apoptosis-inducing ligand，TRAIL)和Bak的表達(dá)而促進(jìn)CD4 T細(xì)胞的凋亡[45,46]，而且高水平的IFN-α還會誘導(dǎo)胸腺內(nèi)細(xì)胞缺陷并干擾T細(xì)胞選擇[47]，并促進(jìn)HIV-1誘導(dǎo)第三群固有淋巴細(xì)胞(group 3 innate lymphoid cell，ILC3)凋亡[48]。因此，IFN-α在HIV-1感染機(jī)體過程中可起到兩種截然不同的作用，既可抑制HIV-1病毒的感染和復(fù)制，又可促進(jìn)HIV-1誘導(dǎo)的T細(xì)胞凋亡[28]，給免疫系統(tǒng)帶來損害。

4 對艾滋病治療的啟示

在HIV-1急性感染期，我們可以充分利用IFN-α的抗病毒作用，比如可將CpG作為接種疫苗時(shí)的輔助藥物，促進(jìn)IFN-α的釋放，增強(qiáng)對HIV-1復(fù)制的抑制作用，誘導(dǎo)較強(qiáng)的T細(xì)胞免疫反應(yīng)，這將有利于對疾病進(jìn)展的控制[49]。在HIV-1慢性感染期，我們應(yīng)抑制pDCs的持續(xù)性激活和IFN-α的產(chǎn)生，比如通過抑制gp120與CD4之間的相互作用[50,51]，或者通過封閉TLR7和TLR9而抑制pDCs的激活，但是有研究發(fā)現(xiàn)TLR7和TLR9的封閉對血漿中IFN-α的分泌和ISGs的表達(dá)、病毒載量和T細(xì)胞激活都沒有明顯影響，這可能與封閉的效果有關(guān)，也可能是因?yàn)榇嬖谄渌梢苑置贗FN-α的細(xì)胞，或者在早期感染中pDCs的激活和IFN-α的釋放并不是促進(jìn)免疫激活的主要因素[52]。

5 小結(jié)

pDCs與HIV-1的相互作用過程十分復(fù)雜：一方面pDCs可通過分泌大量的IFN-α起到抗病毒作用；另一方面pDCs又會產(chǎn)生對機(jī)體不利的影響：pDCs既可通過分泌IFN-α激活機(jī)體免疫反應(yīng)，又可通過分泌IDO誘導(dǎo)Treg產(chǎn)生和Th17降低，最終引起慢性免疫炎癥反應(yīng)，破壞機(jī)體免疫系統(tǒng)，促進(jìn)了疾病的進(jìn)展。因此，我們應(yīng)利用pDCs的特點(diǎn)，尋找既可以增強(qiáng)HIV-1病毒特異性的適應(yīng)性免疫應(yīng)答，又可以抑制慢性免疫反應(yīng)激活的方法，從而發(fā)現(xiàn)抑制HIV-1傳播、調(diào)節(jié)適應(yīng)性免疫的新途徑。

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Interaction of HIV-1 and plasmacytoid dendritic cells

PENG Zhuo-ying，XUE Jing，WEI Qiang

(Comparative Medicine Center, Peking Union College (PUMC) & Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS); Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Key Laboratory of Human Diseases Animal Models, State administration of Traditional Chinese medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing 100021, China)

Plasmacytoid dendritic cells (pDCs) as innate immune cells can produce a large amount of interferon-alpha (IFN-α). During the stage of acute human immunodeficiency virus (HIV) infection, pDCs can inhibit HIV replication by releasing IFN-α and activating adaptive immune responses. In the stage of chronic HIV infection, pDCs play a role in immune suppression by regulating immunocytes and damage of the immune system by depletion of the lymphocytes. Finally, pDCs have influence on the disease progression of acquired immune deficiency syndrome (AIDS).

plasmacytoid dendritic cells; HIV; type I interferon

國家自然科學(xué)基金(青年科學(xué)基金項(xiàng)目，81301437)，科技部重大專項(xiàng)(2014ZX10001001-001-004，2014ZX10001001-002-006)。

彭卓穎，女，碩士研究生，從事實(shí)驗(yàn)動物病毒學(xué)研究工作，E-mail：18810963239@163.com。

魏強(qiáng)，教授，博士導(dǎo)師，研究方向：實(shí)驗(yàn)動物病毒學(xué)，E-mail：weiqiang@cnilas.pumc.edu.cn。

綜述與專論

R-33

A

1671-7856(2017) 06-0077-05

10.3969.j.issn.1671-7856. 2017.06.016

2016-11-09