修回日期: 2005-05-20
接受日期: 2005-05-24
在线出版日期: 2005-07-28
人类免疫缺陷病毒(HIV)主要通过突破黏膜屏障侵入人体. 在全世界范围内大约有90%的HIV感染是通过黏膜发生的. 由于黏膜固有层中存在大量的CD4+CD45RO+ T淋巴细胞, 他们表达HIV的受体CD4和辅助受体CCR5, 是HIV侵入黏膜后优先攻击的靶细胞. 这些细胞为HIV早期繁殖提供场所并为系统扩散制造更多的病毒. 黏膜中HIV及其感染细胞不仅存在于黏膜免疫系统的效应部位, 也大量存在于黏膜免疫系统的诱导部位. HIV感染导致黏膜CD4+ T淋巴细胞快速损耗并进而导致黏膜免疫功能缺陷. 由于绝大多数感染因子都通过黏膜侵入人体, 黏膜免疫功能缺损必然导致机会性感染增加, 最终导致艾滋病的发生和感染者因完全无法控制机会性感染而死亡. 由于黏膜既是HIV侵入机体的主要门户, 又在HIV感染的急性期及随后的整个病理过程中发挥作用, 因此在AIDS疫苗和药物的研究中应重视对HIV黏膜传播的控制.
引文著录: 杨贵波, 邵一鸣. 人类免疫缺陷病毒与黏膜免疫. 世界华人消化杂志 2005; 13(14): 1750-1759
Revised: May 20, 2005
Accepted: May 24, 2005
Published online: July 28, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(14): 1750-1759
- URL: https://www.wjgnet.com/1009-3079/full/v13/i14/1750.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i14.1750
人类免疫缺陷病毒(human immunodeficiency virus, HIV)是获得性免疫缺陷综合征(acquired immunodeficiency syndrome, AIDS), 即艾滋病的致病因子[1].HIV感染是世界卫生组织公布的导致死亡人数最多的病毒感染之一. 在人们开始认识HIV还不足25年的时间里, HIV/AIDS已无情地剥夺了成千上万人的生命. 据世界卫生组织, 在2004年中有约四千万HIV感染者或AIDS患者. 仅2004年AIDS死亡人数就高达300多万, 新发感染者约有500万. 尽管全世界都在致力于寻找预防和治疗HIV感染和AIDS的新措施(高效抗病毒药物和各种疫苗), 然而至今仍然无法根除感染者体内的病毒或完全控制病毒复制, 也尚未治愈过任何一位AIDS患者[2].
HIV属于逆转录病毒科的慢病毒属, 分为HIV-1和HIV-2两型: 前者在全世界范围内广泛流行, 而后者则主要流行于西非. HIV-1主要通过性接触、血液及其制品或污染针具在人群中水平传播, 和在母婴之间垂直传播[3-4]. 原发性HIV-1感染可引起急性逆转录病毒综合征, 其特征为发烧、咽炎、淋巴腺病、肌痛、皮疹和头痛[5]. 在美国约有50%的HIV-1感染者在2-6 wk内出现急性逆转录病毒综合征. 在暴露于HIV-1后, 从血清阳转到发展为AIDS, 感染者平均经过10年左右的无症状期[6-8]. 然而, 有大约5%的感染者在未经任何治疗的情况下可长期保持无症状, 称为长期不进展者(long-term non-progressors, LTNPs). 他们可多年维持低病毒载量、正常的免疫功能和稳定的CD4+ T细胞数[9]. 有趣的是有部分人在通过黏膜反复接触病毒后也不被感染. 表明人体中存在一些尚不清楚的免疫保护机制可以控制或阻止HIV-1感染.
尽管能够被HIV-1感染的人体细胞有多种, 但能支持产毒性感染的细胞(productively infected cells)类型主要是那些被激活过的或记忆性的CD4+ T淋巴细胞和巨噬细胞[10-11].HIV-1抗原特异的CD4+ T淋巴细胞会被优先感染[12].CD4分子是HIV-1进入靶细胞的主要受体[13-14], 他主要表达于部分T淋巴细胞、单核／巨噬细胞和树突状细胞. 但多数研究者认为树突状细胞并不支持产毒性感染. HIV-1的主要辅助受体为CCR5和CXCR4. 但其他分子, 包括GalCer和CCR1、CCR2b、CCR3、CCR8、CX3CR1、Apj、Strl33、Gpr1、Gpr15、ChemR23、RDC1等也可充当HIV-1的受体或辅助受体[15-17].HIV-1的半衰期小于6 h并很可能仅为30 min[18].HIV-1感染过的CD4+T细胞的半衰期平均约为1-1.5 d. 在未经治疗的感染者中, HIV-1每天约要感染2×109细胞. 但由于病毒cDNA被整合入感染细胞的基因组后可长期存在于细胞核内, 使得清除体内病毒的唯一希望是所有感染细胞的死亡. 据估计, 即使在高效抗病毒药物的作用下要清除感染者体内的病毒所需的时间应在60年以上[19]. 而现有的候选疫苗尚未显示出任何可彻底清除这些感染细胞的能力.
对HIV-1感染途径的研究发现, 在HIV-1的传播中, 性接触传播占绝大部分(75-80%)[20]. 因此, 黏膜传播是世界上HIV-1传播的主要途径[21-22], 全球范围内有90%的HIV-1感染是通过黏膜发生的. 另一方面, 不论HIV-1是否通过黏膜侵入人体, 黏膜都是HIV-1繁殖的主要场所. 1998年Veazey et al[23]报道SIV感染恒河猴肠黏膜中CD4+T淋巴细胞很快大量损耗. 在6年之后两个不同的研究组同时发现HIV-1感染者肠黏膜固有层CD4+ T淋巴细胞很快被选择性地耗损, 这种耗损在感染后很快出现并持续存在于感染后的各个时期, 即使在高效抗HIV-1药物治疗期间CD4+T淋巴细胞耗损也同样发生. 表明肠黏膜在整个AIDS病理过程中, 尤其是在感染后很早就起着十分重要的作用. 因此, HIV-1疫苗和药物研究应重视对HIV-1黏膜传播的预防和对黏膜中HIV-1的控制. 可以预期, 能够诱导黏膜免疫保护的AIDS疫苗势必在有效遏制艾滋病的全球蔓延中发挥巨大的作用.
HIV-1传播的途径有多种: 如静脉吸毒者间共用注射针具可将HIV-1从带毒一方传给另一方; 携带HIV-1的血液也可通过输血将病毒传给受血者. 然而随着公共卫生条件的改善, 通过血液及其制品和污染针具的传播会得到有效地控制. 与黏膜相关的传播主要有母婴传播和性接触传播. 自1981年首次发现艾滋病至今, 性传播一直是世界上HIV-1传播的主要方式[20]. 在性传播过程中, 黏膜是HIV-1侵入机体的主要途径[24]. 黏膜接触的病毒主要来自HIV-1携带者的黏膜分泌液、母乳、产道液及精液等体液[25-28]. 这些体液中的病毒以游离的形式存在或位于被感染的细胞之中. 暴露于病毒的黏膜主要为消化道黏膜和泌尿生殖道黏膜.
通过生殖道黏膜传播的HIV-1主要来自感染者的精液或生殖道分泌液. 在感染者的精液中可发现具感染力的游离病毒和带病毒的细胞[29-31]. 原发性感染的HIV-1多为均一的巨噬细胞嗜性病毒, 并为非合胞体诱导(non-syncytium inducing, NSI)表型[32-33]. 近来也有报道发现一些妇女感染的HIV-1为不均一的异源病毒, 而通过性接触使其被感染的男子所带的病毒则为均一的同源病毒[34]. 黏膜传播HIV-1的来源尚有感染的母乳和感染者的唾液等[35]. 虽然通过感染者唾液传播的危险相对很低, 仅1-5%患者唾液中含感染性HIV-1, 但母乳在母婴传播中的机率却较高. 母乳中的一部分病毒以游离的病毒粒子存在, 另一部分存在于感染过的细胞之中. 母乳中的细胞较多, 尤其是感染者的初乳中可能带有大量的感染细胞.
HIV-1进入消化道黏膜的主要途径可能有四种[36]: 即通过微皱褶(microfold, M)细胞、树突状细胞(dendritic cell, DC)、或上皮细胞的转运以及通过上皮屏障裂隙或生理性开放[37]进入黏膜. HIV-1也曾经被发现于男同性恋艾滋病患者直肠黏膜的肠嗜铬(EC)细胞之中[38]. 但HIV-1是否可通过EC细胞进入机体尚无报道. 覆盖于器官性黏膜相关淋巴组织之上的上皮为小结相关上皮(follicle associated epithelium, FAE).M细胞为FAE中的特殊上皮细胞. 这种细胞顶端微绒毛较短、细胞内溶酶体水平较低, 主要功能为摄取和传递抗原[39-40]. 除FAE外, M细胞也被发现于人的结肠和直肠黏膜上皮中. 有研究发现HIV-1可以黏附于小鼠和兔的M细胞顶面[41], 也有电镜观察发现HIV-1病毒粒子位于M细胞内[42]. 因此, 在黏膜物理屏障完整的情况下, HIV-1有可能通过M细胞进入消化道黏膜.
DC细胞为能够激活幼稚T淋巴细胞的专业抗原呈递细胞, 广泛存在于机体各个部位, 包括胃肠道和生殖道黏膜. DC也被发现于大鼠的肠黏膜上皮中, 可能直接接触肠腔内的病原物质[43]. 其在HIV-1黏膜传播和病理过程中的确切作用目前还不清楚. 由于DC细胞表达HIV-1的受体CD4和辅助受体CCR5, 因此HIV-1可以感染DC细胞. 另外, 不同DC细胞表达不同的C类凝集素受体如DC-SIGN(dendritic cell-specific ICAM-3 grabbing nonintegrin, DC-SIGN, 又名CD209).DC-SIGN能高亲合力地与HIV-1的膜蛋白结合[44-46], 因此DC可能充当将HIV-1从黏膜转运到次级淋巴器官的载体[47-49]. 结合于DC表面的HIV-1可长时间保其持感染力, 并能被有效地传递给靶细胞. 有研究表明, 急性感染期SIV(simian immunodeficiency virus)复制可很快见于猕猴生殖道黏膜的Langerhan细胞(Langerhan cells, LC)和组织DC中. 因此, DC可能是最先接触黏膜表面HIV-1的细胞类型之一[50-53], 他们可能通过顺、反感染(cis-infection、trans-infection), 既被HIV-1感染或仅与HIV-1结合, 从而传递HIV-1并促进其产毒性地感染CD4+T淋巴细胞. 因此, DC可能是HIV-1突破黏膜屏障、尤其是生殖道黏膜的主要介导者.
由于研究发现HIV-1能够感染培养的上皮细胞, 通过穿胞作用穿越上皮进入黏膜可能是HIV-1入侵机体的另一途径[54-55]. 曾经有不同的研究者证明HIV-1存在于活体病理解剖的肠黏膜标本的上皮细胞之中[56-57]. 虽然肠上皮细胞并不表达CD4这一HIV-1赖以进入细胞的经典受体分子, 但有研究证明肠上皮细胞可以表达半乳糖苷神经酰胺(GalCer)和CCR5[16-17]. 同时也有研究表明HIV-1可以利用半乳糖苷神经酰胺作为受体感染结肠上皮细胞[58]. 体外研究中也发现HIV-1可以穿越由培养的肠上皮细胞系或子宫内膜细胞系形成的单细胞层. 尽管有报道指出HIV-1可以通过生殖道黏膜进行传播[20,59], 但关于HIV-1如何通过生殖道上皮的机制尚不十分清楚. 生殖道黏膜是否出现溃疡性疾病与HIV-1感染具有显著的相关性, 表明HIV-1可能通过损伤的生殖道黏膜进入体内[60]. 但在动物实验中已经证明, SIV可通过完好的阴道壁复层上皮、阴道颈部的上皮和阴茎部尿道进入体内. 因此, 黏膜上皮本身难以完全阻止HIV-1的入侵.
黏膜是HIV-1感染的主要组织[23]. 体外研究证明: 免疫细胞(CD4+T 淋巴细胞、巨噬细胞等)、消化道和生殖道黏膜上皮细胞系等许多类型的细胞都对HIV-1感染敏感[11,61-65]. 在体内研究中发现, HIV-1产毒性感染(productive infection)的靶细胞主要是已激活的CD4+T淋巴细胞或记忆CD4+T细胞, 另外还有巨噬细胞[10,11,66-69]. 也有报道指出HIV-1可产毒性感染树突状细胞[15,70], 但对此的报道并不一致. 通常在原发感染的早期HIV-1以感染CD4+T淋巴细胞为主, 即使所感染的病毒是M嗜性的病毒. 而随着体内CD4+T淋巴细胞的耗损, 组织中被感染的巨噬细胞会增加.
肠黏膜固有层中存在大量的淋巴细胞和巨噬细胞, 他们都表达HIV-1受体CD4分子. 绝大多数的CD4+T淋巴细胞都是被激活过的或处于静止期的免疫记忆细胞. 由于肠上皮细胞表达CCR5, 利用半乳糖苷神经酰胺为受体和CCR5为辅助受体进入黏膜的HIV-1多为M嗜性. 尽管如此, 由于肠黏膜中CD4+T淋巴细胞表达CCR5而巨噬细胞不表达CCR5[71], 因此HIV-1进入黏膜后首先并且产毒性地感染大量的CD4+T淋巴细胞. 在灵长类动物AIDS模型的研究中, 不论是静脉内注射还是直肠内接种SIVmac251, 在感染后的第3 d, 就可用PCR(polymerase chain reaction)在肠黏膜里检测出SIVmac251的DNA, 每100 000细胞中的拷贝数可达300-15 000个[72].
关于女性患者生殖道中首先被感染的细胞类型的体内研究资料较为缺乏[73]. 在慢性HIV-1感染女性的宫颈组织中, 可发现被HIV-1感染的T淋巴细胞、巨噬细胞和Langerhans细胞[74]. 在SIV感染猕猴的AIDS模型的研究中, Spira et al[53]发现雌性生殖道中最初被感染的细胞为固有膜内的Langerhans细胞. Zhang et al[75]发现主要是CD4+T细胞而非树突状细胞在猴阴道内暴露于SIV 3 d后被感染. Hu et al[52]显示在阴道内暴露SIV的60 min内树突状细胞内有SIV RNA. 近年Gupta et al[73]又使用器官培养模型对此进行了进一步研究, 确定记忆CD4+T细胞为宫颈黏膜感染中首先被感染的细胞. 但人生殖道黏膜中首先被HIV-1感染的细胞是CD4+T淋巴细胞还是树突状细胞尚需进一步研究.
除了CD4+T细胞和巨噬细胞以外, 肠上皮中的其他细胞如肠上皮细胞和弥散内分泌细胞中也可检测出HIV-1的蛋白质或核酸[38,56,76-79]. 但并无报道表明体内这些细胞是否支持病毒的复制. HIV-1主要在激活的CD4+ T淋巴细胞中复制, 与静止期CD4+T淋巴细胞产毒量小相一致. 在HIV-1感染的CD4+T淋巴细胞中, 处于静止期的CD4+T淋巴细胞中所含的病毒RNA比处于激活状态的CD4+T淋巴细胞中的病毒RNA要少5倍左右[75].
对于HIV-1跨越黏膜上皮屏障之后在人体内的扩散速度目前知之甚少. 在灵长类动物AIDS模型的研究中发现, 暴露于黏膜的SIV可局部存在较长时间[75,80]或在24-48 h内出现于收集该区域淋巴的淋巴结内[52,81].
黏膜传播在某种程度上可能与黏膜局部所受的神经内分泌调节有关. 生殖道黏膜的结构受生殖激素的影响而周期性地变化. 在生殖道黏膜传播影响因素的研究中发现生殖激素可影响HIV-1转录[82]. 对月经周期是否影响生殖道中病毒的脱落量的报道尚不一致[83-84]. 在灵长类动物AIDS模型的研究中发现体内植入黄体酮可促进SIV传播, 而雌激素则抑制SIV传播. 可能与这些激素能影响阴道壁厚度或通过IL-2等影响CCR5和CXCR4表达有关[85-86]. 由于胃肠黏膜免疫系统也受神经内分泌的影响[87-88], 而HIV-1也可感染肠黏膜内分泌细胞[38], 因此胃肠神经内分泌对HIV-1黏膜传播的影响值得研究.
影响HIV-1通过黏膜传播的因素较多. 传播者体内的病毒载量、分泌液中的病毒载量、被传播者的黏膜创伤、炎症、溃疡和危险的性行为等都可促进HIV-1的传播. 影响病毒进入生殖道黏膜的因素目前尚不十分清楚. 一些人仅暴露于HIV-1一次就被感染, 而另一些则要在暴露多次之后才被感染 [89]. 尚有一部分人在多次反复暴露之后也不被感染[90]. 可能影响HIV-1通过生殖道黏膜传播的因素较多. 如在妇女体液中的HIV-1的载量、口服避孕药、妊娠、宫颈异位、性传播疾病(STD)、细菌性阴道病(bacterial vaginosis, BV)、保护性黏膜免疫及一些已知或未知的遗传因素[85,91-92]等都与HIV-1通过生殖道黏膜传播有关. 在最近的报道中, Sha et al[93]发现与细菌性阴道病有关的细菌群落可以影响生殖道中HIV-1病毒的脱落量. 病毒本身的特性也与其黏膜传播能力有关. 有研究表明在异性传播中HIV-1 E亚型比B亚型更易通过黏膜传播[94-98]. 此外也有研究者指出A亚型和C亚型HIV-1也可能较易借助于性途径进行传播[99].
特异黏膜免疫保护的重要效应成分包括CTL(cytotoxic T lymphocyte)和为分泌型IgA(S-IgA).HIV-1特异的S-IgA曾经被发现于通过性接触而暴露于HIV-1的未感染者中[100-102]. 例如Clerici et al发现在夫妻中仅一方感染的暴露而未感染者的血清中可以检测到具有中和能力的IgA, 其S-IgA可与gp41上的表位结合[103]. 黏膜IgA也出现于对HIV-1有抵抗力的性工作者和其他暴露而未感染的人中[100,104-107].R5嗜性HIV-1能通过人子宫内膜HIC-1细胞单层, 炎性细胞或递质可促进该过程[108]. 特异的细胞免疫反应也发现于暴露而未感染者的生殖黏膜分泌物中[109-110]. 因此, 黏膜的细胞和体液免疫均有可能影响HIV-1通过黏膜传播.
化学促动因子(chemokine)受体CCR5和CXCR4是HIV-1进入细胞的主要辅助受体. 已报道的其他辅助受体尚有CCR1、CCR2b、CCR3、CXC3CR1等. CCR5-D32突变可影响HIV-1感染. 在美国一男性同性恋人群研究中, CCR5-D32纯合突变占暴露而未感染者的3.6%, 在感染者中未见CCR5-D32纯合突变, 尽管在美国白人中CCR5-D32纯合突变率为1.4%[111].CCR2-V64I突变不影响人对HIV-1的易感性, 但纯合和杂合突变的感染者的AIDS进程和死亡推迟[112-114]. 在对肯尼亚的商业性工作者的研究中发现21-46%的慢速进展者携带该突变[112]. 另一影响AIDS进展的遗传特征涉及SDF-1, CXCR4的主要配体. 已有研究显示SDF-1阻止使用CXCR4为辅助受体的HIV-1感染[115-116]. 突变基因SDF-1 3'a导致SDF-1合成增加, 竞争性抑制T淋巴细胞嗜性HIV-1与细胞的结合. 具有该纯合突变的HIV-1感染者的进展是否减慢尚无一致的结果[117-119], 但在诊断为AIDS后存活时间延长[119]. 尽管遗传因素可以影响HIV-1感染, 但仅是众多影响因素之一.
由于趋化因子可与HIV-1的辅助受体结合, 因此可能阻止HIV-1侵入靶细胞[120]. 在暴露而未感染者中, CD4+ T细胞产生的RANTES, MIP-1a和MIP-1b水平升高, 并抑制巨噬细胞嗜性的HIV-1的复制[121-122]. 在16对仅一方感染HIV-1的异性性伴侣之间, 外周血白细胞所产生的RANTES, MIP-1a, MIP-1b在量上无区别[101]. 另外, 趋化因子及其类似物已用于抗HIV-1药物的应用研究中, T20(enfuvirtide)便是其中之一.
在HIV感染者中, 黏膜功能会受到严重影响, 包括黏膜的细胞和体液免疫应答[123-124]. 因此, 那些黏膜表面经常接触大量感染因子的器官系统, 如消化系统、呼吸系统、尿生殖系统等的正常功能也会受到相应的影响, 如HIV/AIDS肠病和机会性感染导致的呼吸衰竭[125-126]会出现在许多HIV-1感染者之中.
用免疫组织化学[127-132]和流式细胞术[133-135]对黏膜中的淋巴细胞的检测发现, 在HIV-1感染后CD4+/CD8+T细胞比例下降, CD8+T细胞增多. 在HIV-1感染者和SIV感染的非人灵长类动物模型的研究中都发现肠黏膜固有层中的CD4+T淋巴细胞很快减少. 与外周血相比, 肠黏膜中CD4+T淋巴细胞的耗损要更快、更早并更为明显. 这种CD4+T淋巴细胞耗损使固有层中失去了重要的调节性T淋巴细胞, 导致黏膜免疫缺陷. 肠黏膜中CD8+T淋巴细胞的增加主要因为HLA-DR+CD8+T细胞和CD11a+CD8+T细胞亚群的增加[134]. 这些可能是可识别HIV-1抗原的细胞毒性Ｔ淋巴细胞[136-138]. 这些CD8+T细胞可能在控制感染病毒繁殖[139-140]的同时杀死HIV-1的主要靶细胞, 加快CD4+ T淋巴细胞耗损.
Sistig et al[141]对33例HIV-1患者和21例对照者唾液中IgG1, IgG2, IgG3, IgG4, IgA1, IgA2的水平进行了研究, 发现HIV-1阳性患者中IgA2的水平显著降低. 研究表明HIV-1感染者唾液中的IgA具有中和HIV-1的能力[142].HIV-1感染者唾液中的HIV-1-特异的IgA水平与疾病发展的进程有关. 在较早阶段可在血浆和唾液中检测到HIV-1特异的IgA[143], 且多数感染者的抗体可中和利用CCR5为辅助受体的原代病毒[144]. 但在疾病后期IgA水平很低或根本无法检测到. 这种分泌型IgA水平的下降或许与黏膜免疫功能在疾病晚期已出现严重缺陷有关. 另外也有报道表明HIV-1感染者黏膜中HIV-1特异的IgA水平较低[145]. 另有报道称在HIV-1感染者中可诱导出针对CT-B(cholera toxin B)的正常黏膜IgA B细胞反应[146]. 因此, HIV-1感染对黏膜体液免疫反应能力的影响可能存在个体差异.
HIV/AIDS肠病指艾滋病患者的胃肠功能紊乱, 常见症状包括腹泻、吸收不良和体重减轻等, 均频繁见于HIV-1感染病例的报道之中[125,147-149]. 由于在多达30-40%的病例中无可鉴定的肠道病原体, 因此引起这些症状的原因尚不清楚. 在无继发性感染的情况下, HIV-1感染者的小肠也发生萎缩, 并伴有上皮细胞分裂能力低下和肠细胞成熟障碍[150]. 目前认为AIDS肠病可能因机会性感染、炎性反应所产生的细胞因子和HIV-1病毒对肠上皮细胞的直接感染所致[124,151-152]. 由于HIV-1不仅感染免疫细胞也感染体外培养的肠上皮细胞[153-154]. 上皮细胞感染及CD+ T淋巴细胞耗损可直接或间接地破坏黏膜屏障功能的完整性. 有研究表明HIV-1即使不进入肠上皮细胞, 也可通过与细胞表面GalCer结合而影响肠上皮细胞的功能[16-17]. 不仅如此, HIV-1产物Tat蛋白可诱导Caco-2细胞和人结肠黏膜分泌活动并抑制肠细胞分裂[151].
黏膜免疫功能障碍会导致机体对其他病毒、细菌、寄生虫感染的抵抗能力降低. AIDS患者往往伴有多种机会性感染, 如巨细胞病毒感染[155]、各种细菌感染[156]、和寄生虫感染[157]等. 这些感染会进一步影响黏膜免疫功能的完整性.
AIDS疫苗研究一直是HIV/AIDS研究的重点之一. 虽然针对HIV/AIDS的药物研究已经取得了长足的进展, 如自1987年发现第一个抗HIV-1药物至今已有20多种被FDA(food and drug administration)批准用于治疗AIDS的药物. 药物治疗也显著地延长了感染者的寿命并改善了他们的生活质量. 但人们普遍认为疫苗应是防止HIV/AIDS流行最经济有效的最理想的手段, 尤其是在欠发达国家中[158-162]. 自发现HIV-1是AIDS的致病因子以来的二十多年中, 人们对蛋白亚单位疫苗、灭活病毒疫苗、减毒疫苗、活载体重组苗和DNA疫苗以及多种免疫策略等都进行了深入探索[163]. 虽然已进行了的III期临床试验宣告失败, 但目前仍然还有20多种候选疫苗进入临床试验. 在不知这些疫苗是否能有效地预防或治疗HIV/AIDS之前, 探索新的疫苗仍然是HIV/AIDS领域研究的前沿. 成功的经验告诉我们, 黏膜疫苗是黏膜抗感染的有效措施. 由于黏膜在HIV-1感染和病理过程中起着十分重要的作用, 探索黏膜AIDS疫苗便具有特别重要的意义.
基于高危人群的研究发现, 一些人在黏膜反复暴露于HIV-1后仍然为HIV-1检测阴性, 即WB(western blotting)检测HIV IgG阴性, HIV RNA和HIV DNA PCR阴性[164]. 在对这些暴露于HIV-1而未被感染的人群研究中发现了针对HIV-1的特异黏膜免疫反应[21,100], 包括具有中和或阻断HIV-1通过肠上皮细胞的IgA[102,106-107,165]和HIV-1特异的CD4+T辅助细胞和CD8+细胞毒T淋巴细胞[109,166]. 在黏膜自然暴露于HIV-1后能够产生黏膜免疫力而后重复多次暴露也不被HIV-1感染这一现象表明有效的黏膜免疫能够阻断HIV-1的黏膜传播. 由于黏膜免疫可在局部阻止HIV-1黏膜传播和控制通过黏膜进入的HIV-1的系统性扩散. 从而在很大程度上可以避免病毒突变和免疫逃逸的问题. 另一方面, 非黏膜途径侵入机体的HIV-1在黏膜中的持续存在也会被局部免疫控制或清除. 因此黏膜AIDS疫苗对于成功地控制HIV/AIDS的广泛传播将起决定性的作用.
如何诱导有效的抗HIV/AIDS的黏膜免疫保护?用什么样的疫苗通过什么样的途径诱导什么样的免疫反应才能够防治HIV/AIDS是AIDS黏膜疫苗所面临的关键问题. 来自SIV感染猕猴和一些来自HIV-1感染者的数据表明: 具有广泛中和能力的抗体、T淋巴细胞(包括CD4+ T辅助细胞和CD8+细胞毒性T淋巴细胞)和天然免疫都可能在控制HIV/SIV感染中发挥十分重要的作用[100-101,106-107,167-181]. 新的黏膜疫苗策略, 如初始免疫后加强免疫(prime-boost); 使用新一代黏膜佐剂、各种具有相互促进作用的细胞因子、化学促动因子、辅助刺激分子、CpG寡脱氧核苷酸的各种组合; 标靶汇集黏膜淋巴的淋巴结等都在促进黏膜疫苗免疫效果方面显示了一定的作用. 部分疫苗实验在动物体内成功地诱导了黏膜免疫反应. 如Amara et al[182]用DNA疫苗进行初始免疫然后用rMVA(recombinant modified vaccinia virus Ankara)进行加强免疫后可控制黏膜感染并防止AIDS. 另外, 黏膜疫苗在诱导局部免疫的同时也可诱导系统免疫应答[183], 表明黏膜疫苗在提供局部免疫保护作用的同时也可提供系统免疫保护. 目前由于对与HIV-1免疫保护相关的免疫因子知之尚少, 严重阻碍了黏膜AIDS疫苗的研制. 未来应加强相关领域的研究: 如与HIV-1免疫保护有关的天然免疫因子、中和抗体和细胞介导的免疫反应; 诱导长效黏膜免疫记忆的免疫策略以及高效的黏膜佐剂等. 这些研究必将为理性设计黏膜AIDS疫苗提供重要的理论基础.
编辑:张海宁
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