陳夢(mèng)云， 宋早文， 方金勇， 徐玲玲， 趙鐵軍

(浙江師范大學(xué) 化學(xué)與生命科學(xué)學(xué)院,浙江 金華 321004)

人類(lèi)T淋巴細(xì)胞白血病1型病毒的感染復(fù)制及致病機(jī)制研究進(jìn)展*

陳夢(mèng)云， 宋早文， 方金勇， 徐玲玲， 趙鐵軍

(浙江師范大學(xué) 化學(xué)與生命科學(xué)學(xué)院,浙江 金華 321004)

主要針對(duì)人類(lèi)T淋巴細(xì)胞白血病1型病毒(human T-cell leukemia virus type 1，HTLV-1)及其與成人T淋巴細(xì)胞白血病(adult T-cell leukemia，ATL)的關(guān)系，尤其是人類(lèi)T淋巴細(xì)胞白血病1型病毒的感染、復(fù)制及致病機(jī)制進(jìn)行了綜述.HTLV-1屬于逆轉(zhuǎn)錄病毒，它的感染可導(dǎo)致成人T細(xì)胞白血病.HTLV-1病毒主要通過(guò)細(xì)胞與細(xì)胞間接觸進(jìn)行傳播，并通過(guò)促進(jìn)其感染細(xì)胞的增殖增加病毒拷貝數(shù).病毒基因的調(diào)控及宿主免疫系統(tǒng)共同決定了體內(nèi)HTLV-1病毒的載量.病毒編碼的HBZ和Tax蛋白在ATL發(fā)生過(guò)程中發(fā)揮著至關(guān)重要的作用，它們?cè)诠δ苌舷嗷ヅ浜?，共同調(diào)節(jié)病毒的復(fù)制，誘導(dǎo)感染細(xì)胞增殖及病毒傳播.對(duì)于HTLV-1病毒與ATL關(guān)系的深入研究，將對(duì)認(rèn)識(shí)病毒和宿主的相互作用及相關(guān)傳染性疾病的防治帶來(lái)新的啟示.

人類(lèi)T淋巴細(xì)胞白血病1型病毒；成人T淋巴細(xì)胞白血病；HBZ蛋白；Tax蛋白

人類(lèi)T淋巴細(xì)胞白血病1型病毒(HTLV-1)于1980年被首次發(fā)現(xiàn)[1]，它與人類(lèi)免疫缺陷病毒(human immunodeficiency virus，HIV)一樣同屬于逆轉(zhuǎn)錄病毒家族.研究表明，HTLV-1是成人T淋巴細(xì)胞白血病(ATL)的病原因子[2].此外，該病毒還能引發(fā)慢性進(jìn)行性神經(jīng)系統(tǒng)疾病——HTLV-1相關(guān)脊髓炎/熱帶痙攣性癱瘓(HAM/TSP)，以及HTLV-1相關(guān)葡萄膜炎、感染性皮炎等自身免疫疾病[1].全世界大約有一兩千萬(wàn)人感染HTLV-1病毒.該病毒主要流行于日本西南部、非洲、加勒比海地區(qū)和南美洲.我國(guó)感染HTLV-1的人群集中在福建沿海和廣東某些地區(qū)[3].

HTLV-1主要通過(guò)3種途徑傳播：母嬰傳播、性傳播和血液傳播[4].HTLV-1具有一個(gè)顯著特征，即：病毒主要通過(guò)細(xì)胞與細(xì)胞接觸的方式傳播，且感染的細(xì)胞必須是活細(xì)胞，游離病毒顆粒幾乎無(wú)感染能力.在感染HTLV-1的病人體內(nèi)有成千上萬(wàn)的病毒克隆，該病毒不僅存在于外周血中，而且存在于淋巴結(jié)、脾、胸腺等淋巴器官中[5].與之不同，人類(lèi)免疫缺陷病毒HIV既可通過(guò)細(xì)胞和細(xì)胞接觸傳播，又可通過(guò)游離病毒顆粒傳播.

1 HTLV-1的傳播

在HTLV-1主要的3種傳播途徑中，母乳傳播被認(rèn)為是HTLV-1最主要的傳播方式.HTLV-1陽(yáng)性母親的子女中HTLV-1陽(yáng)性率可達(dá)25%，HTLV-1陽(yáng)性?xún)和哪赣H90%為HTLV-1感染者[6].一般認(rèn)為，HTLV-1通過(guò)細(xì)胞與細(xì)胞間接觸的方式傳播(見(jiàn)圖1)，無(wú)細(xì)胞的血漿制品不傳播該病毒.檢測(cè)發(fā)現(xiàn)，母乳和精液等體液中含有大量HTLV-1感染的細(xì)胞.有報(bào)道表明，母乳中含有T細(xì)胞，其中大部分為效應(yīng)T細(xì)胞和記憶T細(xì)胞，且均表達(dá)ICAM-1和LFA1[7]，上述細(xì)胞中可檢測(cè)到HTLV-1病毒.這些結(jié)果表明，HTLV-1感染可能賦予感染細(xì)胞一定的表型.HTLV-1是通過(guò)何種途徑使HTLV-1感染細(xì)胞轉(zhuǎn)變?yōu)樾?yīng)/記憶T細(xì)胞的呢？HTLV-1反義鏈編碼的HBZ蛋白可促進(jìn)效應(yīng)/記憶性T細(xì)胞及調(diào)節(jié)性T細(xì)胞數(shù)量增加[8].在表達(dá)Tax的轉(zhuǎn)基因小鼠中，上述細(xì)胞類(lèi)型則無(wú)明顯的變化.可見(jiàn)，由HTLV-1 HBZ蛋白賦予T細(xì)胞的免疫表型，例如效應(yīng)/記憶性T細(xì)胞、調(diào)節(jié)性T細(xì)胞和粘附增強(qiáng)分子，這些因素對(duì)病毒在體內(nèi)的傳播至關(guān)重要.這也表明，ATL細(xì)胞和HTLV-1感染細(xì)胞的免疫表型由HBZ而非Tax所決定.

圖1 HTLV-1感染及ATL發(fā)生的過(guò)程

HTLV-1是如何通過(guò)血腦屏障并侵入中樞神經(jīng)系統(tǒng)(central nervous system，CNS)呢？最近有研究表明，HTLV-1病毒粒子主要通過(guò)轉(zhuǎn)胞吞作用透過(guò)血腦屏障[9].HTLV-1病毒可感染血腦屏障中樹(shù)突狀細(xì)胞(dendritic cells，DC).感染HTLV-1病毒的樹(shù)突狀細(xì)胞可以遷移到引流淋巴結(jié)，并通過(guò)與T細(xì)胞間形成的病毒突觸將病毒傳遞給CD4 T細(xì)胞[10].在體外，游離病毒顆粒很難感染T細(xì)胞，然而，游離病毒顆?？梢愿腥綝C細(xì)胞.被感染的DC細(xì)胞可以傳播HTLV-1病毒，這表明DC細(xì)胞是病毒在體內(nèi)傳播的媒介[11].粘附因子和共刺激因子的表達(dá)參與形成T細(xì)胞和樹(shù)突狀細(xì)胞之間的免疫突觸[12].

此外，HTLV-1病毒誘導(dǎo)感染細(xì)胞數(shù)量的增加可提高病毒傳播的幾率[13-14].

2 病毒進(jìn)入細(xì)胞及其在細(xì)胞間的傳播

與HIV病毒不同，HTLV-1能夠感染多種類(lèi)型的細(xì)胞，如T淋巴細(xì)胞、B淋巴細(xì)胞、成纖維細(xì)胞和巨噬細(xì)胞等[11,15].其原因在于HTLV-1病毒的受體為細(xì)胞表面普遍表達(dá)的生物大分子[15].據(jù)報(bào)道，HTLV-1病毒的外殼蛋白可與3種細(xì)胞信號(hào)分子，如硫酸乙酰肝素蛋白多糖(HSPG)[16]、神經(jīng)菌毛素1(NRP-1)[17]及葡萄糖轉(zhuǎn)運(yùn)蛋白1型(GLUT-1)[18]相互作用，從而進(jìn)入細(xì)胞.在HTLV-1病毒進(jìn)入細(xì)胞的過(guò)程中，HTLV-1病毒抗原可與這些分子形成復(fù)雜的構(gòu)象.首先，HTLV-1病毒外殼與HSPG結(jié)合，然后與神經(jīng)纖毛蛋白-1結(jié)合形成穩(wěn)定的復(fù)合物.之后，GLUT1與該復(fù)合物互作，并最終促使病毒進(jìn)入宿主細(xì)胞[19].

體外實(shí)驗(yàn)表明，游離的HTLV-1病毒顆粒幾乎沒(méi)有感染能力，而正常細(xì)胞與HTLV-1感染細(xì)胞共培養(yǎng)后更容易感染HTLV-1病毒[20].據(jù)文獻(xiàn)[21]報(bào)道：細(xì)胞接觸所介導(dǎo)的HTLV-1病毒感染效率是病毒粒子所介導(dǎo)感染效率的10 000倍;而對(duì)于HIV病毒，通過(guò)細(xì)胞接觸介導(dǎo)的感染效率僅為病毒顆粒介導(dǎo)感染的2倍.目前普遍被接受的HTLV-1感染機(jī)制有3種：1)病毒學(xué)突觸模型[22];2)生物膜模型[23];3)細(xì)胞導(dǎo)管模型[24].HTLV-1感染細(xì)胞與未感染細(xì)胞接觸后形成突觸，病毒蛋白和RNA通過(guò)細(xì)胞間突觸進(jìn)入靶細(xì)胞，其中膜蛋白ICAM-1和LFA-1共同參與突觸的形成.HTLV-1編碼的Tax蛋白促進(jìn)突觸的形成，且在微管的重定位中起重要的作用[25].通過(guò)上述調(diào)控方式，Tax促進(jìn)病毒通過(guò)細(xì)胞與細(xì)胞間的接觸性傳播[21].此外，也有證據(jù)支持病毒傳播的生物膜模型.HTLV-1感染的T細(xì)胞保留病毒誘導(dǎo)的細(xì)胞質(zhì)基質(zhì)成分，包括膠原蛋白、蛋白聚糖、抗病毒因子及半乳凝素-3等[23]，通過(guò)細(xì)胞接觸，這些病毒組件粘附其他細(xì)胞，誘導(dǎo)相鄰細(xì)胞感染HTLV-1病毒.對(duì)于細(xì)胞導(dǎo)管模型，研究發(fā)現(xiàn)一種p8蛋白，能夠增加T細(xì)胞之間的接觸關(guān)聯(lián)，建立T細(xì)胞網(wǎng)絡(luò)，促進(jìn)HTLV-1病毒的傳播.因此，p8蛋白可誘導(dǎo)細(xì)胞管道，保證病毒傳播，同時(shí)避免宿主的免疫監(jiān)視.目前，p8蛋白也作為HTLV-1病毒治療策略的相關(guān)靶點(diǎn)[24].

3 HTLV-1感染細(xì)胞的克隆性增殖

在體內(nèi)，HTLV-1病毒主要感染CD4 T細(xì)胞，并通過(guò)細(xì)胞與細(xì)胞間接觸及樹(shù)突狀細(xì)胞依賴(lài)的方式進(jìn)行傳播.有研究表明，HTLV-1感染細(xì)胞的早期階段會(huì)形成一個(gè)感染細(xì)胞池[26].運(yùn)用免疫缺陷小鼠模型發(fā)現(xiàn)：HTLV-1病毒感染細(xì)胞一周之后使用逆轉(zhuǎn)錄酶抑制劑泰諾福韋(TDF)或齊多夫定(AZT)處理，并不能阻止或減少HTLV-1的前病毒載量；而在HTLV-1病毒感染的同時(shí)注射TDF或AZT則能有效阻斷HTLV-1病毒的感染[27].這些結(jié)果表明，HTLV-1感染細(xì)胞池在感染的早期階段就產(chǎn)生了.HTLV-1感染后，機(jī)體內(nèi)感染細(xì)胞的克隆化增殖占主導(dǎo)地位.同樣，在臨床實(shí)驗(yàn)也發(fā)現(xiàn)，逆轉(zhuǎn)錄酶抑制劑和整合酶抑制劑的聯(lián)用并不能改變感染者體內(nèi)HTLV-1病毒的載量[28-29].

感染的早期階段，HTLV-1感染細(xì)胞克隆的量受宿主免疫攻擊和病毒基因表達(dá)量?jī)蓚€(gè)因素的共同影響.HTLV-1感染細(xì)胞的克隆在早期階段不穩(wěn)定，但在感染的后期逐漸穩(wěn)定[30]，表明HTLV-1的感染在早期感染階段受宿主的選擇調(diào)控，而后期篩選后的細(xì)胞則會(huì)穩(wěn)定存在于宿主體內(nèi).

HTLV-1為單股RNA病毒.HTLV-1進(jìn)入人體淋巴細(xì)胞后就與其他逆轉(zhuǎn)錄病毒一樣，病毒RNA經(jīng)自身的逆轉(zhuǎn)錄酶作用逆轉(zhuǎn)錄為cDNA，同時(shí)這種前病毒DNA被隨機(jī)整合到宿主細(xì)胞基因組DNA中.

理論上，每個(gè)感染性克隆均有不同的整合位點(diǎn)，可用于分析HTLV-1病毒的克隆形成能力.新一代測(cè)序技術(shù)可以顯示出整合位點(diǎn)的分布情況，也可定量分析感染細(xì)胞中的克隆性增殖情況.研究發(fā)現(xiàn),典型的HTLV-1感染個(gè)體中可能會(huì)出現(xiàn)成千上萬(wàn)個(gè)感染性克隆[31].反向PCR方法已被用于鑒定HTLV-1整合位點(diǎn)[32-33].此外，高通量測(cè)序技術(shù)也可用于分析HTLV-1病毒的克隆形成能力[34].研究發(fā)現(xiàn)，HAM/TSP患者與無(wú)癥狀攜帶者相比具有更高的病毒載量.人們通過(guò)高通量測(cè)序發(fā)現(xiàn)，HAM/TSP患者與無(wú)癥狀攜帶者在單一病毒感染的克隆數(shù)量上無(wú)差異，但HAM/TSP患者中被感染的克隆數(shù)較多[34].相比之下，同時(shí)感染HTLV-1和類(lèi)圓線(xiàn)蟲(chóng)屬或同時(shí)感染HTLV-1和皮炎(IDH)的患者中特定的病毒感染克隆數(shù)目增加[35].另外，值得注意的是，IDH患者和HTLV-1攜帶且感染類(lèi)圓線(xiàn)蟲(chóng)屬的人中，患ATL的人數(shù)相對(duì)較多，而HAM/TSP患者中ATL發(fā)生的機(jī)率并不高[36].因此，克隆豐度及細(xì)胞分裂次數(shù)增多對(duì)于ATL的發(fā)生具有重要的作用.

HTLV-1感染細(xì)胞的分裂受哪些因素調(diào)控？HBZ基因在ATL和HTLV-1感染的細(xì)胞中廣泛表達(dá)，且HBZ具有促進(jìn)細(xì)胞增殖的作用[37].此外，Tax基因可增強(qiáng)有絲分裂抗原受體信號(hào)[38-39].HBZ和Tax促進(jìn)細(xì)胞增殖的機(jī)制相對(duì)比較復(fù)雜.現(xiàn)有研究發(fā)現(xiàn),HBZ和Tax在調(diào)控與腫瘤發(fā)生相關(guān)的信號(hào)通路中具有相反的調(diào)控功能[40](見(jiàn)圖2).例如：Tax可激活A(yù)P-1，NFAT和CREB信號(hào)通路，而HBZ則對(duì)上述信號(hào)通路具有抑制作用[41-42]；另外，Tax可抑制TGF/Smad信號(hào)通路，而HBZ激活該通路[43]；Tax激活經(jīng)典和非經(jīng)典的NF-κB信號(hào)通路[44]，而HBZ選擇性抑制p65介導(dǎo)的經(jīng)典N(xiāo)F-κB途徑；Tax除了可促進(jìn)細(xì)胞增殖外，也可通過(guò)誘導(dǎo)p21和p27蛋白的表達(dá)，從而誘導(dǎo)細(xì)胞的衰老，而HBZ通過(guò)抑制p65的表達(dá)阻滯Tax介導(dǎo)的細(xì)胞衰老[45].除此之外，有報(bào)道表明，HBZ基因可以mRNA形式促進(jìn)T細(xì)胞增殖[37].實(shí)驗(yàn)證實(shí)，HBZ通過(guò)形成二級(jí)莖環(huán)結(jié)構(gòu)上調(diào)E2F1及其靶基因的表達(dá)，促進(jìn)G1/S轉(zhuǎn)換，進(jìn)而促進(jìn)腫瘤細(xì)胞的惡性增殖[46].該研究結(jié)果表明，HBZ可以mRNA和蛋白質(zhì)2種形式參與調(diào)控白血病細(xì)胞的惡性增殖，促進(jìn)成人T細(xì)胞白血病的發(fā)生.

圖2 HBZ與Tax在調(diào)控腫瘤相關(guān)信號(hào)通路中的作用

此外，有報(bào)道表明，HBZ通過(guò)抑制TCF1/LEF-1轉(zhuǎn)錄因子與DNA的結(jié)合從而抑制經(jīng)典Wnt信號(hào)通路，而Tax蛋白則可激活Wnt信號(hào)通路.與之相反，HBZ能有效增強(qiáng)Wnt5a啟動(dòng)子的活性，促進(jìn)其表達(dá)，進(jìn)而活化非經(jīng)典Wnt信號(hào)通路.在胸腺T細(xì)胞的發(fā)育過(guò)程中，Wnt經(jīng)典信號(hào)通路是持續(xù)激活的;而在外周T細(xì)胞中，Wnt非經(jīng)典信號(hào)通路是激活的.上述研究表明，HBZ通過(guò)調(diào)控Wnt信號(hào)通路調(diào)節(jié)外周T細(xì)胞的胞內(nèi)環(huán)境，促進(jìn)HTLV-1病毒的感染.

綜上所述，HBZ和Tax通過(guò)復(fù)雜的相互作用共同調(diào)控著HTLV-1感染細(xì)胞的增殖.

4 病毒基因的轉(zhuǎn)錄調(diào)控

HTLV-1前病毒包括9 032個(gè)堿基對(duì)，具有逆轉(zhuǎn)錄病毒的典型結(jié)構(gòu)，從HTLV-1 5′端的開(kāi)放閱讀框架到3′端,依次為5′LTR-gag-pro-pol-env-pX-3′LTR.HTLV-1前病毒編碼調(diào)控基因(Tax和Rex)及pX區(qū)附屬基因(P12，P13，P30和HBZ)共同參與調(diào)節(jié)病毒的復(fù)制和感染細(xì)胞的增殖[4].轉(zhuǎn)錄過(guò)程中，病毒兩端的5′LTR和3′LTR作為病毒的啟動(dòng)子分別編碼病毒的正鏈和負(fù)鏈.病毒正鏈編碼所有的結(jié)構(gòu)蛋白和病毒基因組RNA，因此,5′LTR的轉(zhuǎn)錄對(duì)病毒的復(fù)制和傳播至關(guān)重要.Tax是HTLV-1正義鏈編碼的一個(gè)調(diào)節(jié)病毒轉(zhuǎn)錄和復(fù)制的核心蛋白，Tax通過(guò)與細(xì)胞轉(zhuǎn)錄因子CREB的相互作用結(jié)合到病毒的啟動(dòng)子5′LTR上[47].5′LTR有3個(gè)21 bp的CRE重復(fù)序列，稱(chēng)為T(mén)ax反應(yīng)元件(TRE).此外，Tax-CREB復(fù)合物還可以招募包括CREB結(jié)合蛋白CBP,P300和p300/CBP相關(guān)因子PCAF在內(nèi)的組蛋白乙?；D(zhuǎn)移酶到病毒5′LTR上，從而促進(jìn)病毒蛋白的表達(dá).除了Tax，一些細(xì)胞信號(hào)元件也可激活5′LTR.例如，通過(guò)激活T細(xì)胞受體信號(hào)可增強(qiáng)5′LTR啟動(dòng)子的活性[39,48].另有研究表明，凋亡信號(hào)也可誘導(dǎo)病毒轉(zhuǎn)錄[49].總之，HTLV-1 5′LTR的激活有助于病毒的傳播，且?guī)椭《咎颖芩拗骷?xì)胞的免疫反應(yīng).

研究發(fā)現(xiàn)：在體內(nèi)，HTLV-1病毒蛋白的復(fù)制往往被抑制[50]；而經(jīng)過(guò)體外培養(yǎng)后，HTLV-1感染細(xì)胞中包括Tax在內(nèi)的病毒蛋白均快速表達(dá)[51].眾所周知，宿主細(xì)胞內(nèi)存在免疫監(jiān)視系統(tǒng)，可通過(guò)監(jiān)視病毒蛋白的表達(dá)從而清除被病毒感染的細(xì)胞.在HTLV-1病毒編碼的病毒蛋白中，Tax是細(xì)胞殺傷T細(xì)胞(CTLs)最主要的靶蛋白[52]，宿主體內(nèi)存在著針對(duì)Tax蛋白的免疫反應(yīng).研究表明，在細(xì)胞體外培養(yǎng)條件下，如果將CD8 T細(xì)胞從外周血單個(gè)核細(xì)胞中去除，HTLV-1感染細(xì)胞中Tax的表達(dá)將上調(diào)[50].此外，病毒5′LTR的轉(zhuǎn)錄被抑制，表明還有其他機(jī)制也參與沉默病毒基因的轉(zhuǎn)錄[53].最近，研究發(fā)現(xiàn)HTLV-1可以通過(guò)自身編碼的蛋白抑制病毒的復(fù)制.病毒蛋白P30和HBZ可通過(guò)與Tax競(jìng)爭(zhēng)性結(jié)合CREB，進(jìn)而抑制HTLV-1病毒的復(fù)制[54].同時(shí)，P30還能抑制Tax/Rex mRNA的表達(dá)[55].

除此之外，DNA甲基化和組蛋白修飾等表觀遺傳學(xué)修飾也參與到沉默HTLV-1基因表達(dá)的過(guò)程中.與HTLV-1不同，HIV的LTR存在較少的CpG位點(diǎn)，但同時(shí)存在脫氧核糖核酸酶超敏位點(diǎn)，這也解釋了為什么HIV LTR能有效抵抗宿主的免疫沉默調(diào)控[56-57].然而，HTLV-1 LTR中存在多個(gè)CpG位點(diǎn).因此,HTLV-1啟動(dòng)子容易被DNA甲基化，從而導(dǎo)致HTLV-1病毒轉(zhuǎn)錄受到抑制.研究發(fā)現(xiàn)，在HTLV-1攜帶者中，HTLV-1前病毒CpG位點(diǎn)的甲基化有升高的趨勢(shì)，且隨著ATL的發(fā)生，甲基化程度明顯上調(diào)[58].由此可見(jiàn)，在ATL細(xì)胞中，Tax的表達(dá)常常因?yàn)镠TLV-1 5′LTR的沉默及5′LTR的損傷而受到抑制[59-60].由于Tax蛋白是殺傷性T細(xì)胞的攻擊靶點(diǎn)，因此，Tax的缺失可以使HTLV-1感染的白血病細(xì)胞有效逃避宿主的免疫攻擊，從而實(shí)現(xiàn)感染細(xì)胞的無(wú)限增殖.最新研究發(fā)現(xiàn)，用組蛋白去乙酰化酶抑制劑丙戊酸鈉(VPA)處理無(wú)癥狀的HTLV-1攜帶者和HAM/TSP病人樣本后，病毒蛋白Tax和Gag蛋白的表達(dá)明顯上調(diào).這表明在病毒攜帶階段，表觀遺傳學(xué)調(diào)控就已經(jīng)參與到抑制病毒的轉(zhuǎn)錄過(guò)程中[61].

相較于5′LTR，3′LTR作為HTLV-1病毒負(fù)鏈的啟動(dòng)子則比較保守和穩(wěn)定[62]，且3′LTR中的CpG位點(diǎn)呈現(xiàn)去甲基化的狀態(tài)，表明3′LTR所引起的反義鏈轉(zhuǎn)錄對(duì)HTLV-1致癌過(guò)程必不可少[58,63].研究發(fā)現(xiàn)，HTLV-1反義鏈編碼HBZ基因.HBZ基因在幾乎所有ATL病人樣本中均持續(xù)高表達(dá).有報(bào)道表明，在ATL中持續(xù)表達(dá)的通用轉(zhuǎn)錄因子SP1與HBZ及JunD可形成復(fù)合物，從而增強(qiáng)HBZ啟動(dòng)子的活性[62].這表明SP1在調(diào)控3′LTR啟動(dòng)子活力、維持HBZ持續(xù)表達(dá)中發(fā)揮重要的作用[64].另有研究發(fā)現(xiàn)，Tax可激活3′LTR啟動(dòng)子的活力[62].然而，Tax的這一調(diào)節(jié)機(jī)制尚不清楚.總之，3′LTR的轉(zhuǎn)錄調(diào)控及HBZ基因的高表達(dá)對(duì)于ATL的發(fā)生至關(guān)重要，其潛在機(jī)制及意義有待進(jìn)一步深入研究.

5 宿主的免疫調(diào)節(jié)及感染細(xì)胞的增殖

HTLV-1前病毒載量主要由病毒的基因調(diào)控及宿主的免疫系統(tǒng)2種因素共同決定[65].如上所述，宿主對(duì)Tax具有很強(qiáng)的免疫反應(yīng)，而對(duì)HBZ的免疫反應(yīng)則較弱.研究發(fā)現(xiàn)，HTLV-1前病毒載量與HBZ的免疫反應(yīng)密切相關(guān).由于宿主對(duì)HBZ的免疫反應(yīng)較弱，從而導(dǎo)致HTLV-1感染個(gè)體中具有較高的病毒載量.人們推測(cè)，HTLV-1病毒通過(guò)不斷的突變及進(jìn)化而降低了宿主免疫系統(tǒng)對(duì)HBZ的免疫反應(yīng)，從而使HBZ蛋白在機(jī)體內(nèi)持續(xù)穩(wěn)定表達(dá)，進(jìn)而通過(guò)HBZ的高表達(dá)促進(jìn)感染細(xì)胞的增殖.與之相反，病毒蛋白Tax在ATL的發(fā)展進(jìn)程中表達(dá)時(shí)限較短暫.雖然Tax對(duì)HTLV-1病毒的復(fù)制和病毒的傳播是十分重要的,然而，由于Tax是機(jī)體免疫反應(yīng)的主要靶點(diǎn)，因此HTLV-1病毒通過(guò)精密的調(diào)節(jié)機(jī)制抑制Tax的表達(dá).因此，HTLV-1正是通過(guò)調(diào)控病毒蛋白的表達(dá)而與宿主免疫調(diào)節(jié)達(dá)到一定的平衡，最終由于長(zhǎng)時(shí)間的遺傳學(xué)和表觀遺傳學(xué)的改變而適應(yīng)宿主體內(nèi)的環(huán)境[5].

6 結(jié) 語(yǔ)

綜上所述，HTLV-1病毒感染可引起成人T細(xì)胞白血病等相關(guān)疾病.HTLV-1病毒主要通過(guò)細(xì)胞與細(xì)胞接觸傳播.病毒蛋白HBZ和Tax通過(guò)協(xié)同調(diào)控病毒的轉(zhuǎn)錄和感染細(xì)胞的增殖而促進(jìn)白血病的發(fā)生.HTLV-1誘導(dǎo)ATL發(fā)生的精確機(jī)制還有待進(jìn)一步研究；而闡明HBZ和Tax的致癌功能和探索靶向HBZ和Tax的ATL治療法，將為白血病的治療提供新的方法和思路.

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(責(zé)任編輯 薛 榮)

Research progress in human T-cell leukemia virus type 1 and its mechanisms of oncogenesis

CHEN Mengyun, SONG Zaowen, FANG Jinyong, XU Lingling, ZHAO Tiejun

(CollegeofChemistryandLifeSciences,ZhejiangNormalUniversity,Jinhua321004,China)

It was summarized the relationship between human T-cell leukemia virus type 1 (HTLV-1) and adult T-cell leukemia (ATL), especially HTLV-1 infection, replication and its mechanisms of oncogenesis. HTLV-1 was a retrovirus that could cause ATL. HTLV-1 transmited mainly by cell-to-cell contact, and it increased copy number of the virus through promoting the proliferation of infected cells. Regulation of viral genes and the host immune system cooperatively determined viral load of HTLV-1. In the developments of ATL, HTLV-1 encoded HBZ and Tax proteins synergistically regulated viral replication and promoted the proliferation of infected cells. Efforts on the researches of HTLV-1 and ATL would give new insights into virus-host interactions and therapy of related diseases.

human T-cell leukemia virus type 1 (HTLV-1); adult T-cell leukemia (ATL); HBZ; Tax

10.16218/j.issn.1001-5051.2017.03.013

?2016-10-25；

2017-02-21

國(guó)家自然科學(xué)基金資助項(xiàng)目(31470262)；浙江省科技廳公益技術(shù)應(yīng)用研究計(jì)劃項(xiàng)目(2015C33149)

陳夢(mèng)云(1991-)，女，安徽宿州人，碩士研究生．研究方向：分子細(xì)胞生物學(xué)．

趙鐵軍．E-mail： tjzhao@zjnu.cn>

R373.9；Q291

A

1001-5051(2017)03-0324-07