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 in vitro 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 in vitro, 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.

IMPORTANCE 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，已经收集了有关控制HIV-1复制的大量信息。但是，仅部分地阐明了对导致HIV DNA储存库遏制的先天机制的了解，并且与指导对储存库遏制或根除的干预措施有关。我们研究了自然杀手（NK）细胞功能特征在自发控制复制的HIV患者（HIV控制器[HIC]）或在进展和抗逆转录病毒治疗后（进展的患者[PP]）对自然复制者的作用。循环CD4 ^+中HIV DNA拷贝数（总数或整数）之间呈负相关观察到NK细胞和NK细胞的功能。诱导干扰素γ（IFN-γ）的产生和NKp46 / NKp30激活受体诱导的表达与储库大小成反比。这种相关性不仅存在于HIC的同质队列中，而且在分析中包括PP时也存在。适应性（NKG2C ⁺ CD57 ⁺）NK细胞特征与储层大小无关。但是，发现一组不同的370个差异表达的转录本是控制HIV DNA库大小的NK细胞功能差异的基础。在原理证明中CD4 ^+的体外实验用HIV-1感染细胞后，具有上述功能/转录特征的纯化NK细胞在体外控制HIV复制和DNA负荷方面的能力分别比其他NK细胞高10倍和30倍。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储库。他们的选择，扩展和/或过继转移可能支持消除HIV-1感染或安全降低抗逆转录病毒治疗水平的策略。

重要性HIV-1感染的最相关特征是其在体内的DNA储存库大小，这可以保证终身感染并在抗逆转录病毒治疗中断后恢复病毒复制。到目前为止，在识别导致HIV-1储存库遏制的因素方面几乎没有成功。在这项研究中，通过研究进行性或非进行性疾病的HIV-1患者的定量总和整合HIV-1 DNA水平和NK细胞，我们观察到诱导性IFN-γ和天然细胞毒性受体（NCR）在特定亚型的患者中表达具有特征性转录特征的NK细胞代表HIV-1储库控制的相关因素。这代表了我们对控制慢病毒库的机制的了解的进步。监控，选择，扩展，