李克雷，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)實驗動物研究所，衛(wèi)生部人類疾病比較醫(yī)學(xué)重點實驗室，國家中醫(yī)藥管理局人類疾病動物模型三級實驗室，新發(fā)再發(fā)傳染病動物模型研究北京市重點實驗室，北京 100021)

CD45分子在HIV-1病毒感染中的作用研究進(jìn)展

李克雷，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)實驗動物研究所，衛(wèi)生部人類疾病比較醫(yī)學(xué)重點實驗室，國家中醫(yī)藥管理局人類疾病動物模型三級實驗室，新發(fā)再發(fā)傳染病動物模型研究北京市重點實驗室，北京 100021)

CD45分子是具有磷酸酶活性的跨膜蛋白，在免疫細(xì)胞中發(fā)揮重要作用。CD45分子對抗原受體信號轉(zhuǎn)導(dǎo)是必需的，并具有調(diào)節(jié)細(xì)胞凋亡的作用，其功能紊亂會導(dǎo)致自身免疫性疾病、免疫缺陷、惡性腫瘤等。CD45分子的結(jié)構(gòu)及其功能與HIV感染之間的關(guān)系是艾滋病研究領(lǐng)域的重要內(nèi)容之一，本文就CD45分子在HIV感染中的作用作一綜述。

CD45；HIV；免疫細(xì)胞

CD45分子是受體蛋白酪氨酸磷酸酶，主要表達(dá)于有核的造血細(xì)胞，主要功能涉及造血細(xì)胞的發(fā)育、活化、衰老和凋亡。CD45對T細(xì)胞的發(fā)育非常重要，如果CD45丟失，那么在胸腺中進(jìn)行的雙陽性選擇會導(dǎo)致細(xì)胞的大量凋亡。此外，CD45作為跨膜分子，在細(xì)胞的信號轉(zhuǎn)導(dǎo)中發(fā)揮重要作用。鑒于CD45是細(xì)胞膜上信號轉(zhuǎn)導(dǎo)的關(guān)鍵分子，在淋巴細(xì)胞的發(fā)育成熟、功能調(diào)節(jié)及信號傳遞中具有重要意義。

1 CD45分子的結(jié)構(gòu)

CD45分子為I型跨膜糖蛋白，其胞內(nèi)區(qū)由D1、D2兩個結(jié)構(gòu)域組成，D1結(jié)構(gòu)域具有酪氨酸磷酸酶活性，D2結(jié)構(gòu)域?qū)1結(jié)構(gòu)域的活性起調(diào)節(jié)作用；其胞外區(qū)包括3個纖維連接蛋白區(qū)、1個半胱氨酸富集區(qū)和3個由mRNA的選擇性剪接得到的結(jié)構(gòu)域，即A、B、C異構(gòu)體。成熟的CD45分子量范圍為180—240 kDa，其最大的異構(gòu)體為CD45RABC，最小的變構(gòu)體為CD45RO，結(jié)構(gòu)如圖1所示[1]。CD45RABC富含O-聚糖和N-聚糖，主要包括A、B、C 3個含O-聚糖的區(qū)域，近膜端區(qū)域含有N-聚糖；另一種剪接形式CD45RO僅含有N-聚糖的近膜端區(qū)域，不含有O-聚糖。

CD45分子上的O-聚糖主要包括兩個核心結(jié)構(gòu)：core-1與core-2[2]，這兩個核心結(jié)構(gòu)可被聚N-乙?；?、唾液酸和海藻糖修飾。與O-聚糖不同，N-聚糖前體合成時具有甘露糖結(jié)構(gòu)，以便其在高爾基體內(nèi)修飾，N-聚糖的這種結(jié)構(gòu)增加了CD45的穩(wěn)定性。糖基化形式在細(xì)胞表面的變化對細(xì)胞存活及功能具有重要影響。

圖1 CD45分子結(jié)構(gòu)示意圖 [19]Fig.1 Schematic diagram of the molecular structure of CD45

2 CD45分子在免疫細(xì)胞中的作用

CD45分子是T細(xì)胞活化所必需的。研究表明TCR或CD3信號刺激不能使CD45表達(dá)缺失的T細(xì)胞增殖和產(chǎn)生細(xì)胞因子[3、4]，并且在CD45缺陷的小鼠模型中也證明CD45在免疫系統(tǒng)中發(fā)揮的重要作用[5、6]。

CD45分子主要是通過蛋白酪氨酸激酶(PTKs)的調(diào)節(jié)來實現(xiàn)對淋巴細(xì)胞的發(fā)育和活化的調(diào)控[7]。PTKs由Src家族(p56lck和p59fyn)、Syr家族(ZAP-70)和Jak家族組成，CD45對p56lck和p59fyn的調(diào)節(jié)在淋巴細(xì)胞活化和信號轉(zhuǎn)導(dǎo)中起重要作用。p56lck和p59fyn分子結(jié)構(gòu)上存在兩個關(guān)鍵的調(diào)節(jié)性酪氨酸磷酸化位點，即一個活化位點和一個抑制位點。CD45通過使活化位點和抑制位點去磷酸化控制Src激酶的活性[8]。在靜息淋巴細(xì)胞中，CD45可以和磷酸基團(tuán)競爭抑制位點并使活化位點去磷酸化，使Src激酶處于非活化狀態(tài)。當(dāng)抗原和受體結(jié)合后，膜蛋白的位置發(fā)生改變，Src激酶向抗原受體方向位移，使Src激酶和CD45分離，活化位點磷酸化而使Src激酶活化，此時CD45發(fā)揮正向調(diào)節(jié)作用。在整合素介導(dǎo)的細(xì)胞粘附過程中，Src激酶和CD45同時向粘附位點位移，活化位點去磷酸化，此時CD45發(fā)揮負(fù)調(diào)節(jié)作用[9、10]。

在淋巴T細(xì)胞的分化過程中，CD45表達(dá)不同的異構(gòu)體，同時細(xì)胞表面的糖基化也發(fā)生改變。T細(xì)胞表面的糖基化形式可用來區(qū)分T細(xì)胞亞群[11]，花生凝集素可與無唾液酸化的core-1O-聚糖結(jié)合，而不能與唾液酸化core-1O-聚糖結(jié)合，而兩者在不同細(xì)胞上存在，前者存在于活化T細(xì)胞，后者存在于初始T細(xì)胞。Core-2O-聚糖存在于不成熟的胸腺細(xì)胞，而不存在于成熟的胸腺細(xì)胞，也存在于活化的T細(xì)胞而非初始T細(xì)胞[12、13]。CD45糖基化對細(xì)胞的功能及存活可產(chǎn)生重要影響。CD45糖基化可調(diào)節(jié)T細(xì)胞的細(xì)胞因子產(chǎn)生[14]，凝集素jacalin可通過特異地與CD45 core-1O-聚糖末端的Galβ1-3GalNAc結(jié)合而活化T細(xì)胞，并誘導(dǎo)T細(xì)胞產(chǎn)生IL-2。Galectin-1也可通過與CD45的結(jié)合調(diào)節(jié)細(xì)胞因子的產(chǎn)生，減少Th1的細(xì)胞因子水平，增加Th2細(xì)胞因子的產(chǎn)生能力[15、16]；CD45糖基化對調(diào)節(jié)細(xì)胞凋亡的易感性，galectin-1結(jié)合CD45誘導(dǎo)T細(xì)胞凋亡，只有當(dāng)T細(xì)胞共表達(dá)C2GnT和CD45的core-2O-聚糖時，galectin-1才能誘導(dǎo)凋亡[17、18]。Galectin-3也可誘導(dǎo)T細(xì)胞凋亡，而這一過程受到CD45分子O-聚糖和N-聚糖的調(diào)節(jié)，galectin-3能誘導(dǎo)CD45+Jurkat細(xì)胞調(diào)亡，但不能誘導(dǎo)CD45-J45.01細(xì)胞凋亡，galectin-3僅能誘導(dǎo)CD45RABC-J45.01細(xì)胞發(fā)生凋亡卻不能誘導(dǎo)CD45RO-J45.01細(xì)胞發(fā)生凋亡，表明CD45分子中的O-聚糖在調(diào)節(jié)galectin-3誘導(dǎo)Jurkat細(xì)胞調(diào)亡中發(fā)揮著重要的作用[19]。

3 CD45在HIV感染中的作用

T細(xì)胞是HIV感染的主要靶細(xì)胞。在HIV感染時，對T細(xì)胞表面分子的變化研究能夠進(jìn)一步闡述HIV的感染機(jī)制。研究表明，表達(dá)CD45RO的CD4+T細(xì)胞更易于結(jié)合HIV-1，而CD45RO-細(xì)胞卻不能結(jié)合[20、21]，并且與HIV在CD4+CD45RABC+初始細(xì)胞內(nèi)復(fù)制程度相比，HIV更容易在CD4+CD45RO+記憶細(xì)胞內(nèi)復(fù)制[22]，當(dāng)HIV感染CD4+CD45RO+細(xì)胞時，CD3/CD28刺激信號引起的細(xì)胞核因子反應(yīng)更強(qiáng)烈，進(jìn)一步說明HIV在CD45RO+細(xì)胞內(nèi)更易復(fù)制[23]。學(xué)者還發(fā)現(xiàn)HIV感染時CD45在T細(xì)胞表面的密度減少，CD4+T細(xì)胞上CD45RA和CD45RO表達(dá)降低，CD45RA在CD8+T細(xì)胞上降低，CD45RO在CD8+T細(xì)胞的表達(dá)升高[24、25]，由于CD45基因的多樣性，使得表達(dá)不同CD45分子的細(xì)胞對病毒的易感性有很大差異。例如將編碼CD45的外顯子進(jìn)行C77G突變后，CD45的mRNA會發(fā)生異常剪切，最終可增加細(xì)胞對HIV的易感性[26]；其他研究也顯示CD45的多態(tài)性與細(xì)胞對HIV的易感性有關(guān)，在非洲烏干達(dá)人中CD45的第4個外顯子有A54G突變，而這種的突變結(jié)構(gòu)降低了HIV的感染頻率[27]，這些都證明CD45與HIV感染密切相關(guān)。

HIV感染T細(xì)胞后可使細(xì)胞發(fā)生凋亡，多種機(jī)制參與了這一過程，其中包括CD45分子介導(dǎo)的細(xì)胞凋亡。由于HIV-1感染T細(xì)胞可干擾CD45的酪氨酸磷酸酶活性和PLCγ的功能，對CD45活性的這種影響與疾病進(jìn)程和細(xì)胞凋亡相關(guān)[28、29]。HIV的Tat、Vpr、Nef、gp120蛋白都可誘導(dǎo)細(xì)胞凋亡[30-33]，但在對gp120誘導(dǎo)凋亡的研究中發(fā)現(xiàn)，gp120通過活化誘導(dǎo)的凋亡涉及到了細(xì)胞的活化[30，34]，由于CD45分子在細(xì)胞活化過程中發(fā)揮重要作用，那么gp120誘導(dǎo)的凋亡可能與CD45有關(guān)。研究表明gp120誘導(dǎo)CD45-的T細(xì)胞凋亡率顯著降低，CD45對gp120誘導(dǎo)凋亡的是通過抑制PI3K/Akt途徑誘導(dǎo)FasL表達(dá)實現(xiàn)的，這表明CD45的胞外區(qū)在調(diào)節(jié)細(xì)胞凋亡過程中發(fā)揮作用[35]，由于CD45胞外區(qū)具有多種糖基化位點，推測CD45的糖基化也在調(diào)節(jié)gp120誘導(dǎo)的凋亡過程中發(fā)揮作用。研究顯示在HIV感染機(jī)體的過程中，一些未感染的T細(xì)胞的CD45的糖基化修飾發(fā)生變化，即無唾液酸化core-1O-聚糖和core-2O-聚糖表達(dá)增加，由于這種變化使得這些未感染細(xì)胞而通過旁觀者效應(yīng)發(fā)生凋亡[36]。

由于HIV潛伏庫的存在，當(dāng)前的AIDS治療方法并不能有效完全清楚體能的HIV病毒，而潛伏感染的CD4+T是HIV治療的主要障礙[37]。HIV主要潛伏在靜息的記憶T細(xì)胞中[38]，靜息記憶T細(xì)胞表面標(biāo)志為CD4+CD45RO+，故對CD45分子的深入研究可能為清除HIV潛伏庫提供新的思路。研究表明，在豬尾獼猴體內(nèi)，表達(dá)于CD4+T細(xì)胞表面的CD45RO 可用于檢測HIV-1 感染模型中潛伏庫細(xì)胞的數(shù)量[39]，并且也有學(xué)者采用抗CD45RO的免疫毒素來清除HIV潛伏庫細(xì)胞，在體外，該免疫毒素清除潛伏感染細(xì)胞效率可達(dá)到99%，且對CD45RA+初始T細(xì)胞和CD8+記憶T細(xì)胞無殺傷作用[40、41]，表明針對CD45RO的靶向藥物設(shè)計具有清除HIV潛伏庫的可行性。

4 展望

CD45是一個重要的跨膜分子，它以其蛋白酪氨酸磷酸酶活性使蛋白酪氨酸激酶的抑制位點的酪氨酸去磷酸化從而使其活化，進(jìn)而在T細(xì)胞活化的信號傳遞中起重要作用。隨著對CD45研究的深入，發(fā)現(xiàn)CD45與多種疾病相關(guān)，人們試圖利用單克隆抗體或藥物阻斷CD45介導(dǎo)的信號轉(zhuǎn)導(dǎo)來阻斷淋巴細(xì)胞的活化，進(jìn)而應(yīng)用于誘導(dǎo)免疫耐受和逆轉(zhuǎn)移植排斥反應(yīng)的研究。但CD45及其結(jié)合蛋白在淋巴細(xì)胞的發(fā)育、增殖和活化過程中的確切作用機(jī)制仍不甚清楚，特別是CD45分子在HIV感染過程中的作用以及對潛伏庫細(xì)胞形成的作用仍需進(jìn)一步研究。

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Research progress on the role of CD45 in HIV-1 infection

LI Ke-lei，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 Re-emerging Infectious Diseases, Beijing 100021, China)

CD45 is a transmembrane molecule with phosphatase activity, and plays a major role in immune cells. CD45 is required for the antigen receptor signal transduction, and attributed as an apoptosis regulator. Impairment of this function may result in autoimmune, immunodeficiency, and malignant diseases. The role of CD45 in HIV-1 infection is one of important research topics. This paper summarizes the research progress on the role of CD45 in HIV-1 infection.

CD45；HIV-1；Immune cells

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

李克雷(1986-)，男，博士生，從事實驗動物病毒學(xué)和免疫學(xué)工作。E-mail： leekelei@126.com。

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

綜述與專論

R-33

A

1671-7856(2017) 06-0082-04

10.3969.j.issn.1671-7856. 2017.06.017

2017-02-21