在早期抗逆转录病毒治疗(ART)及之后,从循环 T 细胞亚群中获得的病毒储存库中 HIV-1 的多样性。

HIV-1 diversity in viral reservoirs obtained from circulating T-cell subsets during early ART and beyond.

机构信息

Molecular Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.

Infectiology, University Hospital Basel, Basel, Switzerland.

出版信息

PLoS Pathog. 2024 Sep 18;20(9):e1012526. doi: 10.1371/journal.ppat.1012526. eCollection 2024 Sep.

Abstract

Even during extended periods of effective immunological control, a substantial dynamic of the viral genome can be observed in different cellular compartments in HIV-1 positive individuals, indicating the persistence of active viral reservoirs. To obtain further insights, we studied changes in the proviral as well as in the viral HIV-1 envelope (Env) sequence along with transcriptional, translational and viral outgrowth activity as indicators for viral dynamics and genomic intactness. Our study identified distinct reservoir patterns that either represented highly sequence-diverse HIV-1 populations or only a single / few persisting virus variants. The single dominating variants were more often found in individuals starting ART during early infection phases, indicating that early treatment might limit reservoir diversification. At the same time, more sequence-diverse HIV reservoirs correlated with a poorer immune status, indicated by lower CD4 count, a higher number of regimen changes and more co-morbidities. Furthermore, we noted that in T-cell populations in the peripheral blood, replication-competent HIV-1 is predominantly present in Lymph node homing TN (naïve) and TCM (central memory) T cells. Provirus genomes archived in TTM (transitional memory) and TEM (effector memory) T cells more frequently tended to carry inactivating mutations and, population-wise, possess changes in the genetic diversity. These discriminating properties of the viral reservoir in T-cell subsets may have important implications for new early therapy strategies, underscoring the critical role of early therapy in preserving robust immune surveillance and constraining the viral reservoir.

摘要

即使在有效的免疫控制延长期间,也可以在 HIV-1 阳性个体的不同细胞隔室中观察到病毒基因组的大量动态,表明活跃的病毒库持续存在。为了获得进一步的见解,我们研究了前病毒以及 HIV-1 包膜(Env)序列的变化,以及转录、翻译和病毒生长活性,作为病毒动力学和基因组完整性的指标。我们的研究确定了不同的储库模式,这些模式要么代表高度多样化的 HIV-1 群体,要么只代表单一/少数持续存在的病毒变异体。单一主导的变体更常见于在早期感染阶段开始接受 ART 的个体中,这表明早期治疗可能会限制储库的多样化。同时,更多样化的 HIV 储库与更差的免疫状态相关,这表现为 CD4 计数较低、方案变更次数较多和合并症更多。此外,我们注意到,在周围血液的 T 细胞群体中,复制能力强的 HIV-1 主要存在于淋巴结归巢的 TN(幼稚)和 TCM(中央记忆)T 细胞中。储存在 TTM(过渡记忆)和 TEM(效应记忆)T 细胞中的前病毒基因组更频繁地携带失活突变,并且在群体水平上,其遗传多样性发生了变化。T 细胞亚群中病毒储库的这些区分特性可能对新的早期治疗策略具有重要意义,强调了早期治疗在保持强大的免疫监测和限制病毒储库方面的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4501/11410260/ddb9b3e2cbe7/ppat.1012526.g001.jpg

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