Longitudinal changes in the transcriptionally active and intact HIV reservoir after starting ART during acute infection.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-05 DOI:10.1128/jvi.01431-24
Julie Janssens, Adam Wedrychowski, Sun Jin Kim, Cordelia Isbell, Rebecca Hoh, Satish K Pillai, Timothy J Henrich, Steven G Deeks, Nadia R Roan, Sulggi A Lee, Steven A Yukl
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引用次数: 0

Abstract

Even in antiretroviral therapy (ART)-suppressed human immunodeficiency virus (HIV)-infected individuals, there are heterogeneous populations of HIV-expressing cells exhibiting variable degrees of progression through blocks to HIV transcriptional initiation, elongation, completion, and splicing. These HIV-transcribing cells likely contribute to HIV-associated immune activation and inflammation as well as the viral rebound that occurs after stopping ART. However, it is unclear whether the blocks to HIV transcription are present before ART and how the timing and duration of ART may affect the clearance of cells expressing HIV transcripts that differ in their processivity and/or presence of mutations. To investigate these questions, we quantified different types of HIV transcripts and the corresponding HIV DNA regions/proviruses in longitudinal blood samples obtained before ART initiation (T1) and after 6 months (T2) and 1 year (T3) of ART in 16 individuals who initiated ART during acute HIV infection. Before ART, the pattern of HIV transcripts suggested blocks to elongation and splicing, and only ~10% of intact proviruses were transcribing intact HIV RNA. During the first 6 months of ART, we detected progressively greater reductions in initiated, 5'-elongated, mid-transcribed, completed, and multiply spliced HIV transcripts. Completed HIV RNA decayed faster than initiated or 5'-elongated HIV RNA, and intact HIV RNA tended to decay faster than defective HIV RNA. HIV DNA and RNA levels at T1-T3 correlated inversely with baseline CD4+ T-cell counts. Our findings suggest the existence of immune responses that act selectively to reduce HIV transcriptional completion and/or preferentially kill cells making completed or intact HIV RNA.IMPORTANCEEven in virologically suppressed HIV-infected individuals, expression of viral products from both intact and defective proviruses may contribute to HIV-associated immune activation and inflammation, which are thought to underlie the organ damage that persists despite suppressive ART. We investigated how the timing of ART initiation and the duration of ART affect the heterogeneous populations of HIV-transcribing cells, including a detailed characterization of the different HIV transcripts produced before ART and the rate at which they decay after ART initiation during acute HIV infection. Even during untreated infection, most cells (~90%) have blocks at some stage of transcription. Furthermore, different HIV transcripts decline at different rates on ART, with the fastest decay of cells making completed and intact HIV RNA. Our results suggest that intrinsic or extrinsic immune responses act selectively to either reduce particular stages of HIV transcription or cause selective killing of cells making particular HIV transcripts.

在急性感染期间开始抗逆转录病毒治疗后转录活性和完整HIV库的纵向变化。
即使在抗逆转录病毒治疗(ART)抑制的人类免疫缺陷病毒(HIV)感染个体中,也存在异质的表达HIV的细胞群体,通过阻断HIV转录起始、延伸、完成和剪接,表现出不同程度的进展。这些hiv转录细胞可能有助于hiv相关的免疫激活和炎症,以及停止抗逆转录病毒治疗后发生的病毒反弹。然而,目前尚不清楚在抗逆转录病毒治疗之前是否存在HIV转录阻滞,以及抗逆转录病毒治疗的时间和持续时间如何影响表达HIV转录本的细胞的清除,这些转录本在其处理能力和/或突变存在方面存在差异。为了研究这些问题,我们量化了16名急性HIV感染期间开始抗逆转录病毒治疗的患者在抗逆转录病毒治疗开始前(T1)、治疗6个月(T2)和1年(T3)后获得的纵向血液样本中不同类型的HIV转录物和相应的HIV DNA区域/前病毒。在抗逆转录病毒疗法之前,HIV转录物的模式显示出对延伸和剪接的阻断,只有约10%的完整原病毒转录完整的HIV RNA。在抗逆转录病毒治疗的前6个月,我们检测到启动的、5'延长的、中间转录的、完成的和多次剪接的HIV转录物逐渐减少。完整的HIV RNA比起始的或5'延长的HIV RNA衰减更快,完整的HIV RNA往往比缺陷的HIV RNA衰减更快。T1-T3阶段的HIV DNA和RNA水平与基线CD4+ t细胞计数呈负相关。我们的研究结果表明,存在选择性地减少HIV转录完成和/或优先杀死生成完整或完整HIV RNA的细胞的免疫应答。重要性即使在病毒学抑制的hiv感染者中,来自完整和缺陷原病毒的病毒产物的表达也可能导致hiv相关的免疫激活和炎症,这被认为是尽管抗逆转录病毒抑制剂仍然存在的器官损伤的基础。我们研究了ART的起始时间和持续时间如何影响HIV转录细胞的异质群体,包括在ART之前产生的不同HIV转录物的详细特征,以及在急性HIV感染期间ART启动后它们衰减的速度。即使在未经治疗的感染中,大多数细胞(约90%)在转录的某个阶段也有阻滞。此外,不同的HIV转录本在ART上以不同的速率下降,产生完整和完整HIV RNA的细胞衰退最快。我们的研究结果表明,内在或外在的免疫反应选择性地减少HIV转录的特定阶段或导致选择性地杀死产生特定HIV转录物的细胞。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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