Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection.
Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection.
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DOI：
10.3389/fimmu.2018.00474
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发表时间：
2018
影响因子：
7.3
通讯作者：
Borrow P
中科院分区：
文献类型：
--
作者：
Peppa D;Pedroza-Pacheco I;Pellegrino P;Williams I;Maini MK;Borrow P
人类巨细胞病毒(HCMV)混合感染在HIV-1队列中非常普遍，是推动持续免疫激活的重要辅助因素，即使在有效的抗逆转录病毒治疗期间也是如此。最近，人巨细胞病毒感染与适应性样自然杀伤(NK)细胞的扩张有关，NK细胞存在表观遗传学改变，影响其细胞功能和表型。在不同感染阶段采集的HIV-1感染者队列中，以健康受试者为对照，研究了HCMV混合感染对NK细胞的异质性及其对不同刺激的功能反应的影响。我们的数据表明，在巨细胞病毒血清阳性的人中，HIV-1感染的NK细胞池发生了重塑，CD56dim NK细胞向成熟的CD57+CD85j+NKG2C+NKG2a−表型转变。缺乏PLZF进一步将适应性NK细胞与其他表达CD57或NKG2C的NK细胞区分开来。HIV感染者的−NK细胞高表达CD2，Siglec-7阴性，并下调关键信号分子SYK和FcεRI-γ，显示出与血清抗体水平相关的适应性NK细胞的特征。值得注意的是，这种适应性特征是在HIV-1早期感染期间检测到的，并在治疗期间持续存在。与传统的NK细胞相比，HIV-1感染者的适应性样NK细胞亚群在Fc受体触发后表现出更多的干扰素-γ的产生，并且他们产生肿瘤坏死因子-α和脱颗粒的能力被保留下来。综上所述，这些数据表明，HMCV感染/重新激活是HIV-1感染的一个标志，在HIV-1感染期间，具有适应性特征的NK细胞在推动NK细胞相对扩张方面发挥了作用。在HIV-1感染者中识别具有保留效应活性的选择性NK亚群提高了开发利用特定NK亚群以实现更好的HIV-1控制的治疗策略的可能性。
Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A− phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF− NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcεRI-γ, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-γ production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-α and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control.