Role of B Lymphocytes In HIV Infection And Pathogenesis

在过去的一年里，我们对HIV疾病背景下的B淋巴细胞免疫发病机制进行了研究，主要集中在1)未成熟/过渡性B细胞过度表达在HIV疾病进展中的机制；2)B细胞凋亡与HIV疾病相关的机制；3)B细胞计数和亚群在抗逆转录病毒治疗(ART)开始后发生的变化；以及4)HIV病毒粒子捕获在淋巴组织中的机制。关于艾滋病毒疾病背景下未成熟/过渡性B细胞增殖机制的第一项研究已经完成，并部分发表在《血液》杂志上。这些细胞的出现与HIV疾病和一种称为特发性CD4+T细胞淋巴细胞减少(ICL)的非HIV免疫缺陷疾病的血清IL-7水平升高和CD4+T细胞计数下降有关。这些观察得出的结论是，与CD4+T细胞淋巴细胞减少相关的动态平衡补偿可能是ICL患者和HIV感染者病情进展中未成熟/过渡性B细胞扩张的根本原因。 在发表在《美国国家科学院院刊》上的第二项相关研究中，我们展示了在患有活动性疾病的HIV感染者中扩大的两种主要B细胞群，即CD10+未成熟/过渡性和CD10-/CD21lo成熟/激活的B细胞中不同的凋亡机制。我们的研究结果表明，CD10+未成熟/过渡性B细胞表达Bcl2家族中支持生存的成员的水平降低，使它们对内源性凋亡高度敏感。相比之下，CD10-/CD21lo成熟/激活的B细胞表达高水平的CD95，使它们对CD95配体介导的细胞凋亡高度敏感，这是一种外在的凋亡途径。在最近发表在《传染病杂志》上的第三项相关研究中，我们证明了上述两种B细胞亚群在患有活动性疾病的艾滋病毒感染者中的过度表达可以通过有效的抗逆转录病毒疗法逆转。有效的抗逆转录病毒疗法还可以使B细胞计数正常化，这表明正在进行的艾滋病毒复制与B细胞的净损失有关，可能是通过增加内源性和外源性凋亡等机制。最后，在发表在《免疫学杂志》上的第四项研究中，我们在一个小鼠模型中调查了细胞外HIV储存库。我们的发现表明，补体受体CD21对于淋巴组织中的HIV病毒粒子捕获是必不可少的，并且抗CD21抗体可以取代结合在CD21表达细胞上的HIV，从而为减轻体内的病毒负担提供了一种潜在的治疗方法。

Over the past year we have pursued studies on B lymphocyte immunopathogenesis in the setting of HIV disease by focusing on 1) mechanisms of immature/transitional B-cell over-expression in advancing HIV disease; 2) mechanisms of B-cell apoptosis associated with HIV disease; 3) changes in B-cell counts and subpopulations that occur following initiation of antiretroviral therapy (ART); and 4) mechanisms of HIV virion trapping in lymphoid tissues. The first study addressing mechanisms of immature/transitional B-cell expansion in the setting of HIV disease has been completed and in part published in Blood. The appearance of these cells has been associated with elevated serum levels of IL-7 and decreased CD4+ T cell counts in both HIV disease and a non-HIV immunodeficiency disease called idiopathic CD4+ T cell lymphopenia (ICL). These observations led to the conclusion that homeostatic compensation associated with CD4+ T cell lymphopenia is likely to be the underlying cause of the expansion of immature/transitional B cells in ICL patients and in HIV-infected individuals with advancing disease. In a second related study, published in the Proceedings of the National Academy of Sciences, we demonstrated distinct mechanisms of apoptosis in the two major B-cell populations expanded in HIV-infected individuals with active disease, namely CD10+ immature/transitional and CD10-/CD21lo mature/activated B cells. Our findings indicate that CD10+ immature/transitional B cells express reduced levels of the pro-survival members of the Bcl-2 family, rendering them highly susceptible to intrinsic apoptosis. In contrast, CD10-/CD21lo mature/activated B cells express high levels of CD95, rendering them highly susceptible to CD95 ligand-mediated apoptosis, an extrinsic pathway of apoptosis. In a third related study, currently under final review in the Journal of Infectious Diseases, we demonstrate that the over-expression of the two aforementioned B-cell subpopulations in HIV-infected individuals with active disease is reversed with effective ART. Effective ART also leads to a normalization of B-cell counts, suggesting that ongoing HIV replication is associated with a net loss of B cells, possibly through mechanisms such as increased intrinsic and extrinsic apoptosis. Finally, in a fourth study published in the Journal of Immunology, we investigated extracellular HIV reservoirs in a mouse model. Our findings indicate that the complement receptor CD21 is essential for HIV virion trapping in lymphoid tissues and that anti-CD21 antibodies can displace HIV bound to CD21-expressing cells, thus providing a potential therapeutic approach for reducing viral burdens in vivo.