Rhein Joshua, Chipman Jeffrey G, Beilman Gregory J, Cromarty Ross, Escandón Kevin, Anderson Jodi, Wieking Garritt, Reichel Jarrett, Batres Rodolfo, Khoruts Alexander, Basting Christopher M, Hinderlie Peter, Davis Zachary B, Eaton Anne, Vaughn Byron P, Eilkhani Elnaz, Safrit Jeffrey T, Soon-Shiong Patrick, Baker Jason V, Klatt Nichole R, Deeks Steven G, Miller Jeffrey S, Schacker Timothy W
Division of Infectious Diseases and International Medicine, Department of Medicine.
Department of Surgery.
JCI Insight. 2025 Jun 3;10(13). doi: 10.1172/jci.insight.190831. eCollection 2025 Jul 8.
BACKGROUNDNK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function and thus may reduce viral reservoirs.METHODSTo determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given 3 subcutaneous 6 mcg/kg doses of N-803. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose.RESULTSWe found a nonstatistically significant approximately 0.50 median log reduction in the frequency of viral RNA+ (vRNA+) and vDNA+ cells/g in the 6 participants with baseline and posttreatment LN biopsies. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells and between NKG2A expression on NK cells and the frequency of vRNA+ cells.CONCLUSIONOur findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.TRIAL REGISTRATIONClinicalTrials.gov NCT04808908.FUNDINGNIH grants 5UM1AI126611, UL1TR002494, R01 AI147912, R35 CA283892, and UM1AI164561.
背景
HIV感染者（PWH）的自然杀伤（NK）细胞功能受损，这阻碍了他们减少淋巴组织（LT）中病毒储存库的潜力。白细胞介素-15超级激动剂N-803已被证明可增强NK细胞和T细胞功能，因此可能减少病毒储存库。
方法
为了确定N-803对淋巴组织的影响，我们进行了一项临床试验，给10名接受有效抗逆转录病毒疗法（ART）的PWH皮下注射3次6 mcg/kg剂量的N-803。我们在基线和最后一剂N-803后获取外周血单核细胞（PBMC）、淋巴结（LN）和肠道活检样本。
结果
在6名有基线和治疗后LN活检样本的参与者中，我们发现病毒RNA+（vRNA+）和病毒DNA+（vDNA+）细胞/克频率的中位数对数减少约0.50，但无统计学意义。在回肠中，我们观察到8/10的参与者vRNA+细胞减少，所有参与者的vDNA+细胞减少。我们还发现NK细胞增殖与vRNA+细胞频率之间以及NK细胞上NKG2A表达与vRNA+细胞频率之间存在显著的负相关。
结论
我们的研究结果表明，N-803可能会减少接受ART治疗的PWH淋巴组织中的HIV储存库，这种效应可能是由增强的NK细胞功能介导的。需要进行对照研究来评估NK细胞疗法对HIV淋巴组织的影响。
试验注册
ClinicalTrials.gov NCT04808908。
资助
美国国立卫生研究院（NIH）资助5UM1AI126611、UL1TR002494、R01 AI147912、R35 CA283892和UM1AI164561。
