Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Division of Medical Oncology, University of Washington, Seattle, WA, United States.
Front Immunol. 2022 May 2;13:879190. doi: 10.3389/fimmu.2022.879190. eCollection 2022.
Long-term antiretroviral therapy (ART) in people living with HIV (PLHIV) is associated with sustained increases in CD4 T-cell count, but its effect on the peripheral blood T-cell repertoire has not been comprehensively evaluated. In this study, we performed serial profiling of the composition and diversity of the T-cell receptor β-chain () repertoire in 30 adults with HIV infection before and after the initiation of ART to define its long-term impact on the repertoire. Serially acquired blood samples from 30 adults with HIV infection collected over a mean of 6 years (range, 1-12) years, with 1-4 samples collected before and 2-8 samples collected after the initiation of ART, were available for analysis. repertoires were characterized high-throughput sequencing of the variable region performed on genomic DNA extracted from unsorted peripheral blood mononuclear cells. Additional laboratory and clinical metadata including serial measurements of HIV viral load and CD4 T-cell count were available for all individuals in the cohort. A previously published control group of 189 repertoires from peripheral blood samples of adult bone marrow transplant donors was evaluated for comparison. ART initiation in PLHIV was associated with a sustained reduction in viral load and a significant increase in repertoire diversity. However, repertoire diversity in PLHIV remained significantly lower than in the control group even after long-term ART. The composition of repertoires of PLHIV after ART also remained perturbed compared to the control cohort, as evidenced by large persistent private clonal expansions, reduced efficiency in the generation of TRB CDR3 amino acid sequences, and a narrower range of CDR3 lengths. Network analysis revealed an antigen-experienced structure in the repertoire of PLHIV both before and after ART initiation that was quite distinct from the structure of control repertoires, with a slight shift toward a more naïve structure observed after ART initiation. Though we observe significant improvement in repertoire diversity with durable viral suppression in PLHIV on long-term ART, the composition and structure of these repertoires remain significantly perturbed compared to the control cohort of adult bone marrow transplant donors.
长期抗逆转录病毒疗法 (ART) 可使 HIV 感染者 (PLHIV) 的 CD4 T 细胞计数持续增加，但它对外周血 T 细胞受体库的影响尚未得到全面评估。在这项研究中，我们对 30 名接受 ART 治疗的 HIV 感染者进行了连续的 T 细胞受体 β 链（TCRβ）库组成和多样性的分析，以明确其对 TCRβ 库的长期影响。对 30 名 HIV 感染者的血液样本进行了连续采集，这些样本是在平均 6 年（范围 1-12 年）的时间内采集的，在接受 ART 治疗前采集了 1-4 份样本，在接受 ART 治疗后采集了 2-8 份样本。利用从未分选的外周血单核细胞中提取的基因组 DNA 进行 TCRβ 高变区的高通量测序，对 TCRβ 库进行了特征分析。对该队列中的所有个体均进行了包括 HIV 病毒载量和 CD4 T 细胞计数的连续测量，获得了额外的实验室和临床元数据。对来自成人骨髓移植供体外周血样本的 189 个 TCRβ 库的先前发表的对照组进行了评估，以进行比较。PLHIV 接受 ART 治疗后，病毒载量持续下降，TCRβ 库多样性显著增加。然而，即使在长期接受 ART 治疗后，PLHIV 的 TCRβ 库多样性仍明显低于对照组。与对照组相比，接受 ART 治疗后 PLHIV 的 TCRβ 库组成也仍然存在紊乱，表现为大量持久的克隆性扩张、TRB CDR3 氨基酸序列生成效率降低以及 CDR3 长度范围变窄。网络分析显示，PLHIV 的 TCRβ 库在接受 ART 治疗前后都存在抗原经验结构，与对照组的结构明显不同，在接受 ART 治疗后，观察到向更幼稚的结构略有转变。尽管我们观察到 PLHIV 在长期接受 ART 治疗后，随着病毒持续抑制，TCRβ 库多样性显著改善，但与成人骨髓移植供体对照组相比，这些库的组成和结构仍然存在明显紊乱。
