虽然人类在治疗艾滋病方面已经取得了惊人的进展，能够通过特定药物延长患者的生命，但找到根治艾滋病病毒（HIV）的方法仍是最艰难的一项挑战。近日，来自美国麻省总医院、麻省理工学院和哈佛大学联合建立的Ragon研究所的科学家们在Nature发表了一篇重磅研究，揭示了HIV在人体内“永生”的机制，为未来治愈艾滋病提供了重要参考。审稿人评价道：“这项研究令人印象深刻，并引起了该领域的极大兴趣。” 该研究所博士后孙玮玮和哈佛医学院讲师高策为论文共同第一作者
寻找治愈艾滋病的方法，远比其他传染病更具挑战性。以丙型肝炎为例，人类已经从束手无策，发展到可以轻松有效地清除体内病毒。但HIV非常狡猾，它们可以潜伏在一些细胞里，很难被揪出来，这种罕见类型的细胞群体形成了一个潜伏库。这意味着，患者必须终身服用抗逆转录病毒药物，才能防止病毒从这些潜伏库里死而复生。为什么不能把潜伏库一网打尽？孙玮玮和高策竭力想破解背后的机制。
这项研究的样本取自8位艾滋病患者。在选择患者时，研究团队有自己的考量，选择了有针对性的研究对象。其中有一位患者很特别，他能够通过自身免疫反应来控制感染（通常称这类人为精英控制者），其余7位患者则接受了5~10年的抗逆转录病毒治疗。
本项研究借助单细胞测序技术同时测出细胞内部DNA和细胞表面蛋白质的表达情况。他们发现，这种包含完整HIV基因组的宿主细胞表面一些特定蛋白的表达量非常高，比普通细胞，甚至其他包含HIV、但HIV基因组部分缺失的的宿主细胞都要高很多。
本项研究最大的亮点就是能够把不同类型的被HIV感染的细胞给区分开，为根除这些具有威胁性的细胞提供了可能性。这是该领域从未做过的事情。同期，蒙特利尔大学免疫学专家Nicolas Chomont在Nature上还发表了一篇对这项研究的评论文章。另外一篇发表在Trends in Immunology上的文章也专门评论了这项成果，引起广泛关注。
实验室成员合照，高策（第一排左一），孙玮玮（第二排右二）。
附文献信息：
Title：Phenotypic signatures of immune selection in HIV-1 reservoir cells
Abstract：Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.
来源：病毒学界