Aggarwal Heena, Khan Lubina, Chaudhary Omkar, Kumar Sanjeev, Makhdoomi Muzamil Ashraf, Singh Ravinder, Sharma Kanika, Mishra Nitesh, Lodha Rakesh, Srinivas Maddur, Das Bimal Kumar, Kabra Sushil Kumar, Luthra Kalpana
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Front Immunol. 2017 Dec 1;8:1697. doi: 10.3389/fimmu.2017.01697. eCollection 2017.
Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) ( = 20) and progressors ( = 18). Eight of these progressors were followed up at 6-12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.
据报道，HIV-1感染个体存在多种B细胞缺陷，包括B细胞亚群的变化、多克隆B细胞活化和耗竭，在不到10%-20%的感染人群中可诱导产生广泛中和抗体。HIV-1疾病在儿童中的进展比成人更快。树突状细胞（DC）上表达的B淋巴细胞刺激因子（BLyS）是B细胞稳态的关键调节因子。了解DC如何影响B细胞表型和功能（病毒中和），进而影响感染儿童的HIV-1疾病结局，对于制定恢复B细胞功能的干预策略至关重要。在本研究中，共招募了38名垂直传播的HIV-1感染且未接受抗逆转录病毒治疗（ART）的儿童和25名血清阴性对照。根据CD4细胞计数和感染后的年份，将感染儿童分为长期无进展者（LTNP）（n = 20）和进展者（n = 18）。其中8名进展者在接受ART后6-12个月进行了随访。通过流式细胞术分析DC、B细胞亚群的百分比（%）以及DC上BLyS的表达。通过酶联免疫吸附测定（ELISA）测量B细胞生长因子的血浆水平，并使用TZM-bl试验测定病毒中和活性。与血清阴性对照相比，HIV-1感染的进展者中髓样DC（mDC）、浆细胞样DC的比例（%）较低，且mDC上BLyS的表达较高。与血清阴性对照相比，进展者中幼稚B细胞、静息记忆B细胞的比例较低，而成熟活化的组织样记忆B细胞的比例较高。与血清阴性对照相比，进展者的血浆中白细胞介素-4（IL-4）、白细胞介素-6（IL-6）、白细胞介素-10（IL-10）和免疫球蛋白A（IgA）水平较高。进展者和LTNP的血浆免疫球蛋白G（IgG）水平高于血清阴性对照，表明在疾病的所有阶段均存在高丙种球蛋白血症。进展者血浆中高浓度的BLyS与较差的病毒中和活性呈正相关。有趣的是，在随访中，未接受治疗的进展者在接受ART后，静息记忆B细胞增加，同时血浆BLyS水平降低，这与病毒中和的改善相关。这是第一项表明在HIV-1感染儿童中，血浆BLyS水平的降低与B细胞功能恢复（就病毒中和而言）相关的研究。
