大约20-30％的HIV-1感染个体develop broadly neutralizing antibodies（BNABS）经过多年的感染，但是知道如何在疫苗接种环境中诱导这些BNAB仍然难以捉摸。研究天然HIV-1感染中BNAB的发展可能会揭示如何通过疫苗引起BNAB。
在先前的研究中，有证明BNAB的发展与表型类似的免疫学特征有关，该患者在发生自身免疫性疾病的患者中已经看到，包括周围的T卵泡助手（TFH）细胞的较高频率[1,2], lower levels of T regulatory (Tregs) cells and an increased frequency of autoreactive antibodies in the plasma.
These findings suggest that HIV-1 infected individuals who generate bnAbs may have less robust immune regulation of their antibody responses but the exact events that precede bnAb development during HIV-1 infection remain unclear. In addition to Tfh and Tregs as key immune adaptive controllers of antibody responses, natural killer (NK) cells, known for their role as effector lymphocytes of the innate immunity, also have immunomodulatory effects and appear to promote and/or maintain adaptive immune responses in inflammatory/autoimmune conditions and infections[3,4].
To understand the underlying mechanisms that lead to bnAb development,布拉德利等。对开发BNABS（BNABS+）的HIV-1感染个体的外周血单核细胞（PBMC）进行了比较转录组分析，并将其与未产生BNAB反应的HIV-1感染个体进行了比较（BNABS-）。
In this study, the authors found that the geneRAB11FIP5, which encodes for a Rab effector protein associated with recycling endosomes, is overexpressed in the NK cell population of bnAbs+ individuals. Moreover,RAB11FIP5expression was positively correlated with the breadth of antibody neutralization in HIV-1 infected individuals.
Overexpression ofRAB11FIP5与NK细胞功能的改变有关，该功能显示出细胞因子释放降低（IFNγ和TNFα）和脱粒（CD107A）。NK细胞在BNABS+个体中的功能改变与其NK细胞的疲惫表型有关，尤其是通过其效应子的重新分布，杀死NK细胞群（CD56DIM）朝着厌氧的NK细胞种群（CD56-），该细胞群（CD56-）直接与之相关RAB11FIP5expression and the breadth of neutralization.
应考虑疫苗接种策略以限制自然杀伤细胞反应，以促进广泛中和抗体的开发。
Based on these results the authors theorize that the altered functionality of the NK cells may lead to the preservation of the Tfh cell compartment in bnAbs+ individuals leading to a better development of antibody responses. In agreement with this hypothesis, Bradley等。showed that activated NK cells from healthy individuals can reduce the Tfh cell population and subsequently impair B cell help体外.
这些发现强调了NK细胞作为驱动BNAB开发的TFH细胞反应的关键调节剂之一。因此，疫苗接种策略应考虑限制NK细胞反应以促进BNAB发育。为了实现这一目标，需要了解NK细胞对TFH细胞的调节是否仅限于HIV-1感染和自身免疫性，还是在健康个体中也会发生。
未来的疫苗接种研究除了B和T细胞外，还应检查通过免疫触发的NK细胞反应，并将这些发现与感染后观察到的反应进行比较。为了限制免疫过程中NK细胞功能，未来的研究应进一步了解BNABS+个体中的NK细胞功能障碍以及如何诱导这种情况。
Another approach to consider is to target the specific mechanisms leading to Tfh depletion by NK cells. Finally, anti-IL-15 antibodies have shown to mediate NK cells depletion [5,6]并可能增强BNAB的生产。
The work by布拉德利等.has considerably increased our understanding of the role of innate immune system in the development of acquired immunity, which opens new doors to regulate the humoral response and broadly neutralizing antibody development by HIV-1 vaccination.
注释