抗逆转录病毒疗法对原发性 HIV 感染患者自然杀伤细胞功能的影响及其与治疗中断后病毒反弹和 HIV DNA 的关系。

Impact of antiretroviral therapy in primary HIV infection on natural killer cell function and the association with viral rebound and HIV DNA following treatment interruption.

机构信息

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Etcembly Ltd, Harwell Campus, Didcot, United Kingdom.

出版信息

Front Immunol. 2022 Aug 30;13:878743. doi: 10.3389/fimmu.2022.878743. eCollection 2022.

DOI:10.3389/fimmu.2022.878743

PMID:36110857

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9468877/

Abstract

Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56 NK cells, Tim-3 expression in CD56 NK cells, IFN-γ expressed by CD56 NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56 and CD56 NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56 NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56 NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound.

摘要

自然杀伤 (NK) 细胞在控制 HIV 复制方面发挥着关键作用，对 HIV 储存库的大小和抗逆转录病毒治疗 (ART) 停止后病毒反弹的可能性有潜在的下游影响。因此，了解原发性 HIV 感染 (PHI) 如何破坏 NK 细胞功能，以及这些功能如何通过早期 ART 恢复，这一点非常重要。我们研究了在 PHI 期间开始 ART 对 7 名特征明确的参与者在治疗开始时（基线）、3 个月、1 年和 2 年的表型和功能性 NK 细胞标志物的影响，并与 HIV 阴性志愿者进行了比较。然后，我们研究了在 SPARTAC 试验中 44 名在 48 周治疗后停止 ART 的个体中，与 ART 相关的那些 NK 细胞特性如何不同地影响病毒反弹时间和 HIV DNA 水平，这些个体在 PHI 期间开始 ART。在接受 2 年治疗的 7 名 HIV 感染者 (PWH) 和 HIV 未感染者之间存在显著差异的 NK 细胞标志物包括 CD56 NK 细胞中的 NKG2C 水平、CD56 NK 细胞中的 Tim-3 表达、CD56 NK 细胞在 IL-12/IL-18 刺激后表达的 IFN-γ以及 CD56 和 CD56 NK 细胞中 Eomes-/T-bet+的分数。在探索 44 名 SPARTAC 参与者停止 ART 后的病毒反弹时间时，没有单个 NK 表型标志物与控制相关。较高水平的 IL-12/IL-18 介导的 NK 细胞脱颗粒在基线时与治疗中断后病毒反弹时间较长相关 (P=0.028)。此外，我们发现 HIV DNA 水平较低的个体中 CD56 NK 细胞的分数较高 (P=0.048)。CD56 NK 细胞中的 NKG2A 和 NKp30 水平在 HIV DNA 水平较低的患者中较高（p=0.00174，r=-0.49 和 p=0.03，r=-0.327，分别），而 CD27 水平在 HIV DNA 水平较高的患者中较高（p=0.026）。这些数据表明，HIV 感染对 NK 细胞功能具有异质性影响，ART 后存在混合的解决情况，尽管 NK 细胞可能影响 HIV DNA 水平和病毒反弹时间，但没有单个 NK 细胞标志物定义延迟的病毒反弹。