Fell Sallie L, Nemphos Sydney M, Prusak James E, Green Hannah C, Miller Jordyn, Rowan Samuel Q, Valencia Natalie, Tatum Coty, Barnes Mary B, Allers Carolina, Scheuermann Sarah, Goff Kelly, Krzykwa Clara, Rowe Lori A, Maness Nicholas J, Moström Matilda J, Hensley-McBain Tiffany, Doyle-Meyers Lara, Kaur Amitinder, Manuzak Jennifer A
Division of Immunology, Tulane National Primate Research Center, Covington, LA, United States.
Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States.
J Immunol. 2025 Sep 1;214(9):2307-2324. doi: 10.1093/jimmun/vkaf100.
Modern antiretroviral therapy (ART) regimens have revolutionized the management of human immunodeficiency virus (HIV) and transformed it from a life-threatening disease to a manageable chronic condition. Despite the durable viral suppression associated with ART adherence, people with HIV (PWH) continue to experience chronic immune activation and inflammation, which has been linked with increased risk of developing non-acquired immunodeficiency syndrome (AIDS) comorbidities, including cardiovascular disease, liver disease, or neurocognitive disorders. Importantly, the mechanisms underlying establishment and maintenance of immune activation in ART-treated PWH remain incompletely defined. Here, we used a nonhuman primate model to evaluate associations between markers of systemic immune activation and peripheral neutrophils in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), both before and after ART. As expected, peripheral frequencies of activated CD4+ and CD8+ T cells were elevated during acute SIV infection and returned to baseline levels following ART initiation. Neutrophil dynamics were impacted during acute SIV infection, including decreased peripheral neutrophil frequencies, increased neutrophil degranulation, and the potential for increased neutrophil extracellular trap (NET) formation. Treatment with ART mitigated these inflammatory neutrophil effector functions. Finally, frequencies of HLA-DR+ CD4+ and CD8+ T cells were significantly positively correlated with frequencies of inflammatory CD62Ldim neutrophils and plasma levels of myeloperoxidase, a component of neutrophil granules. Taken together, these data indicate that neutrophil activity and systemic T cell activation are correlated during acute SIV and early ART. Our work provides insight into associations between neutrophil dynamics and immune activation during HIV/SIV in the context of ART.
现代抗逆转录病毒疗法（ART）方案彻底改变了人类免疫缺陷病毒（HIV）的治疗方式，将其从一种危及生命的疾病转变为一种可控制的慢性病。尽管坚持ART可实现持久的病毒抑制，但HIV感染者（PWH）仍持续经历慢性免疫激活和炎症，这与发生非获得性免疫缺陷综合征（AIDS）合并症（包括心血管疾病、肝脏疾病或神经认知障碍）的风险增加有关。重要的是，接受ART治疗的PWH中免疫激活的建立和维持的潜在机制仍未完全明确。在此，我们使用非人灵长类动物模型来评估在接受ART治疗之前和之后，系统性免疫激活标志物与感染猿猴免疫缺陷病毒（SIV）的恒河猴（RMs）外周中性粒细胞之间的关联。正如预期的那样，在急性SIV感染期间，活化的CD4+和CD8+ T细胞的外周频率升高，并在开始ART后恢复到基线水平。中性粒细胞动态在急性SIV感染期间受到影响，包括外周中性粒细胞频率降低、中性粒细胞脱颗粒增加以及中性粒细胞胞外陷阱（NET）形成增加的可能性。ART治疗减轻了这些炎症性中性粒细胞效应功能。最后，HLA-DR+ CD4+和CD8+ T细胞的频率与炎症性CD62Ldim中性粒细胞的频率以及中性粒细胞颗粒成分髓过氧化物酶的血浆水平显著正相关。综上所述，这些数据表明在急性SIV感染和ART治疗早期，中性粒细胞活性与系统性T细胞激活相关。我们的工作为在ART背景下HIV/SIV感染期间中性粒细胞动态与免疫激活之间的关联提供了见解。
