Marras Francesco, Casabianca Anna, Bozzano Federica, Ascierto Maria Libera, Orlandi Chiara, Di Biagio Antonio, Pontali Emanuele, Dentone Chiara, Orofino Giancarlo, Nicolini Laura, Taramasso Lucia, Magnani Mauro, Marincola Francesco M, Wang Ena, Moretta Lorenzo, De Maria Andrea
Center for Excellence in Biomedical Research, University of Genova, Genoa, Italy.
Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
J Virol. 2017 Nov 14;91(23). doi: 10.1128/JVI.00647-17. Print 2017 Dec 1.
The size of lentiviral DNA reservoirs reflects the effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication. Understanding the innate mechanisms contributing to containment of the HIV DNA reservoir, however, are only partly clarified and are relevant to guiding interventions for reservoir containment or eradication. We studied the contribution of natural killer (NK) cell functional features in HIV patients controlling replication either spontaneously (HIV controllers [HIC]) or after progression and antiretroviral treatment (progressor patients [PP]). An inverse correlation between HIV DNA copy numbers (either total or integrated) in circulating CD4 cells and NK cell function was observed. Induced interferon gamma (IFN-γ) production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only for a homogeneous cohort of HIC patients but also when PP were included in the analysis. Adaptive (NKG2C CD57) NK cell features were not associated with reservoir size. However, a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV DNA reservoir size. In proof-of-principle experiments of CD4 cell infection with HIV-1, purified NK cells with the above-mentioned functional/transcriptional features displayed 10- and 30-fold higher abilities to control HIV replication and DNA burdens , respectively, than those of other NK cells. Thus, NK cells with a specific functional and transcriptional signature contribute to control of the HIV reservoir in CD4 cells. Their selection, expansion, and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment. The most relevant feature of HIV-1 infection is represented by its DNA reservoir size in the body, which guarantees lifelong infection and resumption of virus replication after antiretroviral treatment interruption. So far, there has been little success in the identification of factors contributing to HIV-1 reservoir containment. In this study, by studying quantitative total and integrated HIV-1 DNA levels and NK cells in HIV-1 patients with either progressive or nonprogressive disease, we observed that inducible IFN-γ and natural cytotoxicity receptor (NCR) expression in a specific subset of NK cells with a characteristic transcriptional signature represents a correlate for HIV-1 reservoir control. This represents an advance in our understanding of the mechanism(s) that controls the lentivirus reservoir. Monitoring, selection, expansion, and adoptive transfer of these NK cells may allow monitoring of treatment efficacy and the likelihood of reservoir control and may support protocols for HIV-1 eradication.
慢病毒DNA储存库的大小反映了针对慢病毒的免疫反应的有效性。到目前为止，已经收集了大量关于HIV-1复制控制的信息。然而，对有助于控制HIV DNA储存库的先天机制的理解仅得到部分阐明，并且与指导针对储存库控制或根除的干预措施相关。我们研究了自然杀伤（NK）细胞功能特征在自发控制复制（HIV控制者[HIC]）或进展及抗逆转录病毒治疗后（进展期患者[PP]）的HIV患者中的作用。观察到循环CD4细胞中HIV DNA拷贝数（总拷贝数或整合拷贝数）与NK细胞功能呈负相关。诱导的干扰素γ（IFN-γ）产生以及NKp46/NKp30激活受体诱导的表达与储存库大小呈负相关。这种相关性不仅在一组同质的HIC患者中存在，而且在分析中纳入PP时也存在。适应性（NKG2C CD57）NK细胞特征与储存库大小无关。然而，发现一组独特的370个差异表达转录本是控制HIV DNA储存库大小的NK细胞功能差异的基础。在HIV-1感染CD4细胞的原理验证实验中，具有上述功能/转录特征的纯化NK细胞分别比其他NK细胞表现出高10倍和30倍的控制HIV复制和DNA负荷的能力。因此，具有特定功能和转录特征的NK细胞有助于控制CD4细胞中的HIV储存库。它们的选择、扩增和/或过继转移可能支持根除HIV-1感染或安全降低抗逆转录病毒治疗强度的策略。HIV-1感染最相关的特征由其在体内的DNA储存库大小表示，这保证了终身感染以及抗逆转录病毒治疗中断后病毒复制的恢复。到目前为止，在确定有助于控制HIV-1储存库的因素方面几乎没有取得成功。在本研究中，通过研究进展性或非进展性疾病的HIV-1患者中HIV-1 DNA总量和整合水平以及NK细胞，我们观察到具有特征性转录特征的特定NK细胞亚群中可诱导的IFN-γ和自然细胞毒性受体（NCR）表达代表了HIV-1储存库控制的一个相关因素。这代表了我们对控制慢病毒储存库机制的理解的一个进展。这些NK细胞的监测、选择、扩增和过继转移可能允许监测治疗效果以及储存库控制的可能性，并可能支持HIV-1根除方案。
