HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, United States of America.
PLoS One. 2020 Nov 19;15(11):e0242448. doi: 10.1371/journal.pone.0242448. eCollection 2020.
The Duffy Antigen Receptor for Chemokines (DARC)-null trait, common among persons of African descent and associated with lower absolute neutrophil counts (ANCs), may be linked to increased risk to certain infections including HIV-1 but the underlying causes are poorly understood. We hypothesized that DARC-null-linked neutropenia may negatively impact neutrophil immunoregulatory modulation of other immune cells such as natural killer (NK) and CD8+ T cells leading to altered phenotype, functionality and homeostatic activity of these immune cells. HIV-1 uninfected (n = 20) and HIV-1 chronically infected (n = 19) participants were assessed using multi-parametric flow cytometry to determine NK and CD8+ T cell counts, phenotypic profiles, and cytokine production and degranulation. Annexin V and carboxyfluorescein succinimidyl ester (CFSE) staining were used to examine NK cell survival and NK cell and CD8+ T cell proliferation respectively. Participants were genotyped for the DARC-null polymorphism using allelic discrimination assays and ANCs were measured by full blood count. In HIV uninfected individuals, a reduction of total NK cell counts was noted in the absence of DARC and this correlated with lower ANCs. HIV uninfected DARC-null subjects displayed a less mature NK cell phenotype. However, this did not translate to differences in NK cell activation or effector functionality by DARC state. Whilst HIV-1 infected subjects displayed NK cell profiling that is typical of HIV infection, no differences were noted upon DARC stratification. Similarly, CD8+ T cells from HIV infected individuals displayed phenotypic and functional modulation that is characteristic of HIV infection, but profiling was unaffected by the DARC-null variant irrespective of HIV status. Overall, the data suggests that the DARC-null polymorphism and lower ANCs does not impede downstream cytolytic cell priming and functionality.
趋化因子受体 Duffy（DARC）缺失表型在非洲裔人群中较为常见，与绝对中性粒细胞计数（ANC）降低有关，可能与某些感染（包括 HIV-1）的风险增加有关，但潜在原因尚不清楚。我们假设 DARC 缺失相关的中性粒细胞减少可能会对中性粒细胞对其他免疫细胞（如自然杀伤（NK）和 CD8+T 细胞）的免疫调节功能产生负面影响，导致这些免疫细胞的表型、功能和稳态活性发生改变。我们使用多参数流式细胞术评估了 20 名未感染 HIV-1 的参与者和 19 名慢性 HIV-1 感染者的 NK 和 CD8+T 细胞计数、表型特征以及细胞因子产生和脱颗粒情况。使用 Annexin V 和羧基荧光素琥珀酰亚胺酯（CFSE）染色分别检测 NK 细胞的存活和 NK 细胞和 CD8+T 细胞的增殖情况。使用等位基因鉴别检测对 DARC 缺失多态性进行基因分型，并通过全血计数测量 ANC。在未感染 HIV-1 的个体中，DARC 缺失与总 NK 细胞计数减少相关，且与 ANC 降低相关。未感染 HIV-1 的 DARC 缺失个体表现出 NK 细胞更不成熟的表型。然而，这并没有转化为 DARC 状态对 NK 细胞激活或效应功能的差异。虽然 HIV-1 感染的个体表现出与 HIV 感染相关的 NK 细胞表型，但在 DARC 分层时没有发现差异。同样，来自 HIV 感染个体的 CD8+T 细胞表现出与 HIV 感染相关的表型和功能调节，但无论 HIV 状态如何，DARC 缺失变体都不会影响其表型。总的来说，数据表明 DARC 缺失多态性和 ANC 降低不会阻碍下游细胞毒性细胞的激活和功能。
