Role of B Lymphocytes In HIV Infection And Pathogenesis

在过去的一年里，我们一直在进行HIV疾病背景下B淋巴细胞免疫发病机制的研究，重点是1）未成熟/过渡期B细胞过度表达在HIV疾病进展中的机制; 2）与HIV疾病相关的B细胞凋亡机制; 3）抗逆转录病毒治疗（ART）开始后发生的B细胞计数和亚群的变化;（4）HIV病毒粒子在淋巴组织中的捕获机制。第一项针对HIV疾病背景下未成熟/过渡性B细胞扩增机制的研究已经完成，并部分发表在《血液》杂志上。这些细胞的出现与HIV疾病和称为特发性CD 4 + T细胞淋巴细胞减少症（ICL）的非HIV免疫缺陷疾病中IL-7血清水平升高和CD 4 + T细胞计数降低相关。这些观察结果得出的结论是，与CD 4 + T细胞淋巴细胞减少症相关的稳态补偿可能是ICL患者和疾病进展的HIV感染个体中未成熟/过渡期B细胞扩增的根本原因。 在第二项相关研究中，发表在《美国国家科学院院刊》上，我们证明了在活动性疾病的HIV感染个体中扩增的两种主要B细胞群中细胞凋亡的不同机制，即CD 10+未成熟/过渡型和CD 10-/CD 21 lo成熟/活化B细胞。我们的研究结果表明，CD 10+未成熟/过渡期B细胞表达Bcl-2家族的促生存成员的水平降低，使它们对内在凋亡高度敏感。相反，CD 10-/CD 21 lo成熟/活化的B细胞表达高水平的CD 95，使它们对CD 95配体介导的细胞凋亡（细胞凋亡的外源性途径）高度敏感。在第三项相关研究中，目前正在传染病杂志上进行最后审查，我们证明，在患有活动性疾病的HIV感染个体中，上述两种B细胞亚群的过度表达被有效的ART逆转。有效的ART还导致B细胞计数正常化，这表明正在进行的HIV复制与B细胞的净损失有关，这可能是通过诸如增加的内在和外在细胞凋亡的机制。最后，在《免疫学杂志》上发表的第四项研究中，我们研究了小鼠模型中的细胞外HIV储库。我们的研究结果表明，补体受体CD 21是必不可少的HIV病毒粒子捕获在淋巴组织和抗CD 21抗体可以取代HIV结合的CD 21表达细胞，从而提供了一个潜在的治疗方法，减少体内病毒的负担。

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.