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)過五年多時間完成的一項研究顯示,，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)生機制,，提示改善胸腺功能或為艾滋病治療新思路,。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間控制在測不出的水平之下,，仍有約5%-30%的患者CD4+T免疫細胞數(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”,，其機會性感染發(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)生機制是國際上艾滋病領(lǐng)域近年來的研究熱點。
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例作為研究對象,，觀察其以開始治療為起點,、3年持續(xù)治療過程中CD4+T細胞的純真亞群、記憶亞群,、胸腺新生亞群（CD31）,、凋亡亞群及激活亞群等五個細胞亞群的改變趨勢。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免疫細胞的個數(shù)從開始的每微升164±78個增加到444±100個，接近于正常值500,，其中純真亞群平均增加每微升130±72個,。相比之下，免疫應(yīng)答不好的患者血漿中CD4+T免疫細胞的個數(shù)從開始的每微升29±33個增加到194±75個,，其中純真亞群平均只增長了每微升33±23個,，增幅遠低于前者。進一步觀察二者在胸腺新生細胞CD31占CD4+T細胞的百分比,，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”對增加胸腺新生細胞亞群所起作用不大；胸腺新生細胞與艾滋病患者CD4+T淋巴細胞增長呈正相關(guān),，在艾滋病患者免疫功能重建中起決定作用,，而胸腺功能衰竭會導(dǎo)致免疫學(xué)無應(yīng)答組患者CD4+T純真細胞亞群無顯著增長。
李太生教授介紹說,，這一發(fā)現(xiàn)的重要意義在于,，通過早期檢測艾滋病患者CD4+T淋巴細胞計數(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間后才能確定,。針對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,，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.
