為什么經(jīng)過長期正規(guī)“雞尾酒”治療的艾滋病患者中，仍有少數(shù)患者的病情得不到理想控制,，免疫功能無法重建,？北京協(xié)和醫(yī)院李太生等經(jīng)過五年多時(shí)間完成的一項(xiàng)研究顯示，艾滋病患者免疫功能能否重建,，主要取決于CD4+T細(xì)胞群中胸腺新生亞群的數(shù)量,，這一發(fā)現(xiàn)解釋了艾滋病“免疫學(xué)無應(yīng)答”的發(fā)生機(jī)制，提示改善胸腺功能或?yàn)榘滩≈委熜滤悸?。相關(guān)論文上周發(fā)表在國際著名的《Clinical Infectious Diseases》（臨床傳染病雜志）上,，是艾滋病研究領(lǐng)域的又一重要突破。
上世紀(jì)90年代科學(xué)家關(guān)于艾滋病研究領(lǐng)域最重要的成就在于找到“雞尾酒療法”和提出艾滋病人免疫功能重建理論,，使降低艾滋病發(fā)生率,、病死率成為可能。但隨著研究深入和治療時(shí)間延長,，人們發(fā)現(xiàn),，在保證良好依從性的前提下接受“雞尾酒治療”后，血漿病毒載量較長時(shí)間控制在測(cè)不出的水平之下,，仍有約5%-30%的患者CD4+T免疫細(xì)胞數(shù)量未出現(xiàn)顯著增長,，研究者們將這類艾滋病患者定義為“免疫功能重建不全”或“免疫學(xué)無應(yīng)答”,，其機(jī)會(huì)性感染發(fā)生率、艾滋病相關(guān)疾病發(fā)病率及病死率等均高于“免疫學(xué)應(yīng)答良好”的患者,。因此，艾滋病抗病毒治療后的“免疫學(xué)無應(yīng)答”的發(fā)生機(jī)制是國際上艾滋病領(lǐng)域近年來的研究熱點(diǎn),。
協(xié)和醫(yī)院研究組從病例庫中篩選出抗病毒治療后免疫學(xué)無應(yīng)答者17例和免疫學(xué)應(yīng)答良好者13例作為研究對(duì)象,，觀察其以開始治療為起點(diǎn)、3年持續(xù)治療過程中CD4+T細(xì)胞的純真亞群,、記憶亞群,、胸腺新生亞群（CD31）、凋亡亞群及激活亞群等五個(gè)細(xì)胞亞群的改變趨勢(shì),。結(jié)果發(fā)現(xiàn),，經(jīng)過三年有效抗病毒治療，免疫應(yīng)答好的患者血漿中CD4+T免疫細(xì)胞的個(gè)數(shù)從開始的每微升164±78個(gè)增加到444±100個(gè),，接近于正常值500,，其中純真亞群平均增加每微升130±72個(gè)。相比之下,，免疫應(yīng)答不好的患者血漿中CD4+T免疫細(xì)胞的個(gè)數(shù)從開始的每微升29±33個(gè)增加到194±75個(gè),，其中純真亞群平均只增長了每微升33±23個(gè)，增幅遠(yuǎn)低于前者,。進(jìn)一步觀察二者在胸腺新生細(xì)胞CD31占CD4+T細(xì)胞的百分比,，結(jié)果發(fā)現(xiàn)：免疫應(yīng)答好的患者該比例治療前為12.6%±7.4%，治療三年時(shí)為13.9%±5.5%,，無明顯變化,；免疫無應(yīng)答的患者該比例治療前為2.8%±1.7%，治療三年時(shí)為3.7%±2.5%,，亦無明顯變化,。以上數(shù)據(jù)表明：無論是免疫應(yīng)答好的患者，還是免疫無應(yīng)答的患者,，經(jīng)典的“雞尾酒療法”對(duì)增加胸腺新生細(xì)胞亞群所起作用不大,；胸腺新生細(xì)胞與艾滋病患者CD4+T淋巴細(xì)胞增長呈正相關(guān)，在艾滋病患者免疫功能重建中起決定作用,，而胸腺功能衰竭會(huì)導(dǎo)致免疫學(xué)無應(yīng)答組患者CD4+T純真細(xì)胞亞群無顯著增長,。
李太生教授介紹說，這一發(fā)現(xiàn)的重要意義在于,，通過早期檢測(cè)艾滋病患者CD4+T淋巴細(xì)胞計(jì)數(shù)和胸腺新生比例,，即可甄別出免疫功能重建不全者，而無需等到治療一段時(shí)間后才能確定,。針對(duì)免疫功能重建不全患者,，新治療策略要在持續(xù)“雞尾酒”治療的同時(shí),，努力提高其胸腺功能。中藥研發(fā)可沿著提高胸腺功能的思路展開,。(生物谷 Bioon.com)
doi:10.1093/cid/cir552
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Reduced Thymic Output Is a Major Mechanism of Immune Reconstitution Failure in HIV-Infected Patients After Long-term Antiretroviral Therapy
Taisheng Li, Ning Wu, Yi Dai, Zhifeng Qiu, Yang Han, Jing Xie, Ting Zhu, and Yanling LiBackground. Approximately 20% of human immunodeficiency virus type 1 (HIV-1)--infected adults do not normalize their CD4+ T lymphocytes after long-term effective highly active antiretroviral therapy (HAART). The mechanistic basis for this failure is unclear.
Methods. Seventy-four patients were followed up regularly for 3–7 years. Patients with undetectable plasma viral load (<50 copies/mL) for over 12 months were further classified into 2 groups: (1) immunological nonresponders, whose CD4+ T-cell count was <200/μL or <20% compared with baseline; and (2) immunological responders, whose CD4+ T-cell count was >300/μL or >30% compared with baseline.
Results. Compared with 17 immunological responders, 13 immunological nonresponders had a lower magnitude of naive CD4+ T-cell increase, a lower percentage of recent thymic immigrants (CD31+%), and a higher percentage of activated CD8+ T cells. Furthermore, unlike CD4+ T cells, which increased along with the decrease of viral load, the percentage of recent thymic immigrants (CD31+%) had little change in the majority of patients. These data were fit into a mathematical model, , from which we deduced that the initial rate of CD4+ T-cell restoration is associated significantly with the percentage of recent thymic immigrants (CD31+%).
Conclusions. Our data indicate that the failure to restore CD4+ T-cell count following HAART was associated primarily with a defect in recent thymic immigrants, which suggests the existence of thymus exhaustion.
