Long Brian R, Ndhlovu Lishomwa C, Oksenberg Jorge R, Lanier Lewis L, Hecht Frederick M, Nixon Douglas F, Barbour Jason D
Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, USA.
J Virol. 2008 May;82(10):4785-92. doi: 10.1128/JVI.02449-07. Epub 2008 Feb 27.
A flurry of recent reports on the role of activating and inhibitory forms of the killer cell immunoglobulin-like receptors (KIR) in natural killer (NK) cell activity against human immunodeficiency virus type 1 (HIV-1) have yielded widely divergent results. The role of the activating NK receptor encoded by the KIR3DS1 allele and its putative ligands, members of the HLA class I Bw4Ile80 cluster, in early HIV-1 disease is controversial. We selected 60 treatment-naïve adults for study from the OPTIONS cohort of individuals with early HIV-1 infection in San Francisco. We performed NK cell functional assays measuring gamma interferon (IFN-gamma) and CD107a expression by NK cells in the unstimulated state and after stimulation by the major histocompatibility complex class I-deficient 721.221 B-lymphoblastoid cell line. In addition, we measured CD38 expression (a T-cell activation marker) on T and NK cells. Persons who have at least one copy of the KIR3DS1 gene had higher IFN-gamma and CD107a expression in the unstimulated state compared to those who do not possess this gene. After stimulation, both groups experienced a large induction of IFN-gamma and CD107a, with KIR3DS1 carriers achieving a greater amount of IFN-gamma expression. Differences in effector activity correlating with KIR3DS1 were not attributable to joint carriage of HLA Bw4Ile80 and KIR3DS1. We detected a partial but not complete dependence of KIR3DS1 on the members of B58 supertype (B57 and B*58) leading to higher NK cell function. Possessing KIR3DS1 was associated with lower expression of CD38 on both CD8(+) T and NK cells and with a loss or weakening of the known strong associations between CD8(+) T-cell expression of CD38 mean fluorescence intensity and the HIV-1 viral load. We observed that possessing KIR3DS1 was associated with higher NK cell effector functions in early HIV-1 disease, despite the absence of HLA Bw4Ile80, a putative ligand of KIR3DS1. Carriage of KIR3DS1 was associated with diminished CD8(+) T-cell activation, as determined by expression of CD38, and a disruption of the traditional relationship between viral load and activation in HIV-1 disease, which may lead to better clinical outcomes for these individuals.
最近一系列关于杀伤细胞免疫球蛋白样受体（KIR）的激活型和抑制型在自然杀伤（NK）细胞抗1型人类免疫缺陷病毒（HIV-1）活性中作用的报告，得出了大相径庭的结果。由KIR3DS1等位基因编码的激活型NK受体及其假定配体，即HLA I类Bw4Ile80簇成员，在HIV-1早期疾病中的作用存在争议。我们从旧金山早期HIV-1感染个体的OPTIONS队列中选取了60名未接受过治疗的成年人进行研究。我们进行了NK细胞功能检测，测量未刺激状态下以及经主要组织相容性复合体I类缺陷的721.221 B淋巴母细胞系刺激后NK细胞中γ干扰素（IFN-γ）和CD107a的表达。此外，我们还测量了T细胞和NK细胞上CD38的表达（一种T细胞激活标志物）。与不拥有KIR3DS1基因的人相比，至少有一份KIR3DS1基因拷贝的人在未刺激状态下IFN-γ和CD107a的表达更高。刺激后，两组的IFN-γ和CD107a均大幅诱导，KIR3DS1基因携带者的IFN-γ表达量更高。与KIR3DS1相关的效应活性差异并非归因于HLA Bw4Ile80和KIR3DS1的共同携带。我们检测到KIR3DS1对B58超型（B57和B*58）成员存在部分但非完全的依赖性，从而导致更高的NK细胞功能。拥有KIR3DS1与CD8(+) T细胞和NK细胞上CD38的低表达相关，并且与CD8(+) T细胞CD38平均荧光强度表达与HIV-1病毒载量之间已知的强关联的丧失或减弱有关。我们观察到，在HIV-1早期疾病中，尽管缺乏KIR3DS1的假定配体HLA Bw4Ile80，但拥有KIR3DS1与更高的NK细胞效应功能相关。KIR3DS1的携带与CD8(+) T细胞激活的减弱有关，这是通过CD38的表达确定的，并且破坏了HIV-1疾病中病毒载量与激活之间的传统关系，这可能会使这些个体获得更好的临床结果。
