记忆性Th17细胞在HIV长期潜伏感染中的作用与机制

HIV-1 persists in cellular reservoirs despite effective antiretroviral therapy, which presents the major barrier for HIV eradication. Novel HIV-1 cellular reservoirs and intrinsic mechanisms for their long-term persistence are poorly defined. As one small subset of T helper cells with important immune functions, memory Th17 cells are reported to possess the trait of longevity and homeostatic proliferation with stem cell-like signature, which endows memory Th17 cells the possibility to be a potential cellular reservoir along with treatment. Our preliminary data has shown memory Th17 cells are more susceptible to HIV compared with other types of helper T cells. Combined the above evidence, it has indicated that HIV-1 may employ Th17 cells as a preferred reservoir for promoting long-term viral persistence, which has been poorly elucidated. We will detect the levels of HIV DNA and replication-competent virus production in sorted memory Th17 and non-Th17 memory cells from HIV infected patients longitudinally, who have been treated with suppressive antiretroviral therapy for at least 5 years. Phylogenetic studies will be conducted to deeply reveal the virological feature of viral sequences in the genome of memory Th17 cells compared with those in early and present plasma. Furthermore, little is known about the intrinsic mechanisms and factors influencing the maintenance of memory Th17 cells as a HIV cellular reservoir. We will explore the impact of IL-7 and IFN-α on cell-associated HIV DNA and RNA as well as the function of memory Th17 cells, such as proliferative capacity for self-renewal, anti-apoptotic gene expression and the profile of apoptotic proteins. Targeting long-term memory Th17 cells would be therapeutically meaningful for HIV eradication.

抗病毒治疗仍无法清除感染者的HIV，HIV细胞潜伏库的存在是艾滋病无法治愈的重要原因，发现新的HIV细胞潜伏库、探索其维持机制和影响因素，是清除HIV潜伏库的前提。记忆性Th17细胞是辅助T细胞的亚群，尽管数量少，却具有HIV潜伏库细胞的重要特征：在机体长期存活并稳态增殖。我们前期研究显示，记忆性Th17细胞对HIV的易感性显著高于其它辅助T细胞，提示其很可能是重要HIV细胞潜伏库。本项目以抗病毒治疗有效的HIV感染者为研究对象，通过检测治疗前、治疗1年和5年以上的记忆性Th17细胞HIV DNA和产毒能力、细胞相关HIV与血浆HIV序列分析以及IL-7和IFN-α对其增殖和存活的影响，揭示治疗有效的HIV感染者记忆性Th17细胞内HIV的病毒学特征和细胞功能特性，明确其是否是重要HIV细胞潜伏库及其维持机制和影响因素，为探索艾滋病治愈靶点提供重要科学依据。

HIV-1在CD4 T细胞中长期存活是HIV-1感染的重要特征，HIV-1潜伏库也是艾滋病无法治愈的重要原因。发现新的HIV细胞潜伏库、探索其维持机制和影响因素，是清除HIV潜伏库的前提。记忆性Th17细胞是辅助T细胞的亚群，具有HIV-1潜伏库细胞的重要特征：在机体长期存活并稳态增殖。本研究发现Th17细胞对有效抗病毒治疗的HIV-1感染者潜伏库的贡献大于其他Th细胞群，Th17细胞亚群随着治疗时间延长对HIV-1潜伏库的贡献增加。通过系统进化分析，HIV-1感染者CCR6+Th17细胞群及CD32-CCR6+Th17细胞均出现一致序列，提示Th17细胞及其亚群可能携载病毒在HIV感染者体内长期存在，并以克隆增殖的机制维持其HIV潜伏库大小，是HIV-1细胞潜伏库存在的重要证据。Th17细胞高表达CD32与细胞高活化和病毒高水平复制有关，是HIV感染和潜伏的重要特征。另外，作为重要一群干细胞样记忆性T细胞（TSCM细胞）一部分，Th17SCM细胞亚群数量在HIV-1感染者显著降低，与抗病毒治疗后免疫恢复和免疫活化水平显著相关，急性期治疗后Th17SCM细胞明显恢复，可能导致其对HIV潜伏库的贡献逐渐增加。以上结果显示，研究结果强调了Th17细胞对HIV-1抗病毒治疗后潜伏库的存在具有重要的贡献。Th17细胞在HIV-1感染者中活化水平和高表达CD32等重要免疫学特征显示其在HIV-1潜伏感染、疾病进展和治疗后免疫重建中的重要性，为探索艾滋病治愈靶点提供重要科学依据。