Direct Phenotypical and Functional Dysregulation of Primary Human B Cells by Human Immunodeficiency Virus (HIV) Type 1 In Vitro

BackgroundHuman immunodeficiency virus type 1 (HIV-1) induces a general dysregulation of immune system. Dysregulation of B cell compartment is generally thought to be induced by HIV-related immune activation and lymphopenia. However, a direct influence of HIV-1 particles on B cells was recently proposed as the third pathway of B cells dysregulation. Methods/Principal FindingsWe evaluated the direct and specific consequences of HIV-1 contact on activation, survival, proliferation and phenotype of primary B cells in vitro. Moreover, we examined expression of activation-induced cytidine deaminase (AID) mRNA that is responsible for class switch recombination (CSR) and somatic hypermutation (SHM). Here, we report that changes observed in cellular proliferation, phenotypes and activation of B cells could be caused by direct contact between HIV-1 particles and primary B cells in vitro. Finally, direct HIV-1-derived B cells activation led to the increase of AID mRNA expression and its subsequent CSR function was detected in vitro. Conclusion/SignificanceWe showed that HIV-1 could directly induce primary B cells dysregulation triggering phenotypical and functional abilities of B cells in vitro that could explain in some extent early B-cell abnormalities in HIV disease.

背景 人类免疫缺陷病毒1型（HIV-1）可引发免疫系统的全局性失调。目前学界普遍认为，B细胞区室的失调由HIV相关免疫激活与淋巴细胞减少所介导。然而近期有研究提出，HIV-1病毒颗粒对B细胞的直接作用，可作为B细胞失调的第三条独立途径。
方法与主要结果 我们在体外实验体系中，评估了HIV-1与原代B细胞接触后，对B细胞活化、存活、增殖及表型产生的直接且特异性的影响。此外，我们检测了活化诱导胞苷脱氨酶（activation-induced cytidine deaminase, AID）的mRNA表达水平，该酶是调控类别转换重组（class switch recombination, CSR）与体细胞超突变（somatic hypermutation, SHM）的关键因子。本研究证实，体外实验中观察到的B细胞增殖、表型及活化状态的改变，可由HIV-1病毒颗粒与原代B细胞的直接接触所引发。最终我们发现，HIV-1直接介导的B细胞活化可上调AID的mRNA表达，并在体外实验中检测到其后续的类别转换重组功能变化。
结论与意义 我们的研究表明，HIV-1可在体外直接诱导原代B细胞失调，引发B细胞表型与功能的异常改变，这在一定程度上可解释HIV感染早期出现的B细胞异常现象。