Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.
Front Immunol. 2021 Jun 4;12:647688. doi: 10.3389/fimmu.2021.647688. eCollection 2021.
T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial - but not complete - normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.
T 细胞功能障碍在 HIV 感染后早期发生，影响非艾滋病发病和限制治疗效果。在原发性 HIV 感染（PHI）期间启动的 ART 可以逆转这种功能障碍，但恢复的程度尚不清楚。我们研究了 66 名从早期 PHI 开始接受长达三年 ART 治疗的 HIV 感染者。与未感染 HIV 的对照组相比，早期 HIV 感染的 CD4 和 CD8 T 细胞表现为 T 细胞激活和免疫检查点受体（ICR）PD1、Tim-3 和 TIGIT 的表达增加。三年的 ART 导致 ICR 表达部分 - 但不是完全 - 正常化，个体 ICR 的动态变化不同。对于 HIV 特异性细胞，通过四聚体分选的 CD8 T 细胞进行的表观遗传学分析表明，在 PHI 早期就已经存在慢性 HIV 感染中常见的耗尽的表观遗传特征，并且在 PHI 期间启动 ART 仅导致表观基因组向具有更有利的记忆特征的部分转移。这些发现表明，尽管 PHI 期间启动 ART 会导致显著的免疫重建，但与 HIV 相关的表型和表观遗传变化可能仅部分得到解决。
