HLA-E regulation of NK cell response in HIV. undefined

The contribution of the HLA-E/NKG2X axis in NK-mediated control of HIV infection remains unclear. We have studied the relationship between HLA-E expression and phenotypical as well as functional characteristics of NK cells, in the context of chronic HIV infection and in an in vitro model of acute infection. High viremia in HIV+ individuals was related to increased HLA-E expression, changes in NK subpopulations, specially a reduction of the CD56bright as well as an increase in adaptive NK subpopulation, a reversion of the NKG2A/NKG2C expression ratio and a loss of positive and negative regulation of NK mediated by HLA-E. This was reflected in a lower cytotoxic, degranulation and cytokine production capacity, especially in CD56bright and adaptive NK. In line with these results, HLA-E expression showed a positive correlation with viral growth inhibition at 7 days in an in vitro model of acute infection, that was lost after 14 days culture. We determined that only one out of 11 described HIV-derived HLA-E epitopes increased HLA-E surface stability. In spite of that 8 were capable of increasing degranulation and 3 drove differences in NK-cell mediated cell lysis or cytokine secretion. In conclusion, our results indicate that HLA-E presenting HIV-derived epitopes may sensitize target cells for NK lysis in early infection, whereas prolonged exposure to elevated HLA-E expression levels may lead to NK dysfunction and reduced viral control.

人类白细胞抗原E（Human Leukocyte Antigen E, HLA-E）/NKG2X轴在自然杀伤（Natural Killer, NK）细胞介导的人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）感染控制中的作用仍不明确。本研究针对慢性HIV感染环境与急性感染体外模型，探究了HLA-E表达与NK细胞表型及功能特性之间的关联。HIV阳性个体的高病毒血症与HLA-E表达上调、NK细胞亚群改变密切相关：具体表现为CD56bright亚群减少、适应性NK细胞亚群增多，NKG2A/NKG2C表达比例发生逆转，以及HLA-E介导的NK细胞正负调控功能丧失。这一现象体现在细胞毒活性、脱颗粒功能与细胞因子产生能力的下降，尤其在CD56bright亚群与适应性NK细胞中更为显著。与上述结果一致，在急性感染体外模型中，HLA-E表达在培养7天时与病毒生长抑制呈正相关，但该相关性在培养14天后消失。本研究证实，在已报道的11种HIV来源的HLA-E表位中，仅1种可增强HLA-E的表面稳定性。尽管如此，其中8种可增强脱颗粒功能，另有3种可引发NK细胞介导的细胞裂解或细胞因子分泌差异。综上，本研究结果表明：在感染早期，呈递HIV来源表位的HLA-E可使靶细胞对NK细胞裂解致敏；而长期处于高表达水平的HLA-E则可能导致NK细胞功能障碍，削弱病毒控制能力。