Role of B Lymphocytes In HIV Infection And Pathogenesis

在过去的一年里，我们对B细胞在HIV疾病背景下的研究进行了重点关注：1)未成熟/过渡B细胞在HIV疾病中的扩增机制；2) b细胞亚群对含cpg寡核苷酸刺激的反应；3)开始抗逆转录病毒治疗（ART）后发生的b细胞计数和亚群变化；4) hiv病毒血症个体中存在与hiv相关的b细胞衰竭的证据。在研究HIV疾病背景下未成熟/过渡b细胞扩增机制的第一项研究中，我们调查了接受IL-7治疗的HIV感染者外周血中b细胞亚群的变化，这是一项大型临床安全性试验的一部分。我们的研究结果表明，IL-7本身可以导致外周血中未成熟/过渡B细胞的扩增。这是一个新的观察结果，因为IL-7对人B细胞的直接作用从未在体内建立。

Over the past year we have pursued studies on B cells in the setting of HIV disease by focusing on 1) mechanisms of immature/transitional B-cell expansion in HIV disease; 2) responses of B-cell subpopulations to stimulation with CpG-containing oligonucleotides; 3) changes in B-cell counts and subpopulations that occur following initiation of antiretroviral therapy (ART); and 4) evidence of HIV-associated B-cell exhaustion in HIV-viremic individuals. In the first study addressing mechanisms of immature/transitional B-cell expansion in the setting of HIV disease, we investigated changes in B-cell subpopulations that occurred in the peripheral blood of HIV-infected individuals who received IL-7 as part of a large clinical safety trial. Our findings indicate that IL-7 itself can lead to the expansion of immature/transitional B cells in the peripheral blood. This is a novel observation given that a direct role for IL-7 on human B cells has never been established in vivo. In the second study, published in The Journal of Immunology, we investigated the effect of the DNA oligonucleotide CpG-B, a ligand that binds toll-like receptor 9 expressed on B cells, on the proliferation and effector function of naive and memory B cells isolated from HIV-infected individuals. Overall, our findings indicate that CpG-B, which is currently being considered as an adjuvant in vaccine preparations aimed at augmenting immune responses in immunocompromised individuals, was effective at enhancing the proliferation and secretion of immunoglobulins and cytokines of B cells isolated from HIV-viremic and HIV-aviremic individuals. While certain defects were observed in the memory B-cell compartment of HIV-viremic individuals, nave B cells from both HIV-viremic and HIV-aviremic individuals responded robustly to CpG-B, suggesting that the presence of CpG-B in vaccines could help nave B cells reach the threshold required to productively respond to immunogens. In the third study, published in The Journal of Infectious Diseases, we demonstrate that the over-expression of aberrant B-cell subpopulations, including immature/transitional and hyper-activated B cells, 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, both of which we have previously reported. In the fourth study, published in The Journal of Experimental Medicine, we describe evidence of HIV-associated B-cell exhaustion in an abnormal B-cell compartment that is expanded in the peripheral blood of HIV-infected viremic individuals. This B-cell subpopulation, termed tissue-like memory B cells as a result of their similarities with a recently described tonsillar memory B-cell subpopulation bearing immunoregulatory features, can be distinguished from other B cells by its high expression of the pan B-cell marker CD20 and low expression levels of the complement receptor CD21 and CD27, a classic marker of B-cell memory. Tissue-like memory B cells present in the blood of HIV-viremic individuals exhibit numerous signs of B-cell exhaustion, including increased expression of multiple inhibitory receptors; an altered expression of homing and adhesion receptors similar to that observed with virus-induced T-cell exhaustion; stunted in vivo replication and somatic hypermutation; reduced in vitro proliferation in response to B-cell stimuli; and enrichment of HIV-specific but not nonspecific and recall antigen-specific responses. These findings add to our understanding of why HIV-infected individuals mount a poor antibody response against HIV.