Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals
Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals
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DOI：
10.1172/jci74351
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发表时间：
2014-07-01
影响因子：
15.9
通讯作者：
Fauci, Anthony S.
中科院分区：
文献类型：
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作者：
Kardava, Lela;Moir, Susan;Fauci, Anthony S.
最近，从HIV感染者的记忆B细胞中分离到了几种中和性抗HIV抗体。尽管有大量证据表明HIV疾病中存在B细胞功能障碍，但人们对这些罕见的HIV特异性抗体的来源细胞知之甚少。因此，我们使用HIV包膜gp140和CD4或辅受体(COR)结合位点(Bs)突变探针来评估HIV感染者感染不同阶段外周血B细胞中的HIV特异性反应。与非HIV反应相比，针对gp140的HIV特异性反应在异常的B细胞中丰富，即激活的和耗尽的记忆亚群，这些亚群在未感染的人的血液中基本上不存在。针对Corbs的反应发生得较早，而针对特征良好的中和表位CD4bs的反应则延迟且罕见。静息记忆B细胞(未感染患者的主要亚群)中HIV特异性反应的丰富确实发生在某些感染患者中，这些患者在接受或不接受抗逆转录病毒治疗的情况下，维持较低的血浆病毒血症和免疫激活水平。转录分析证实了HIV特异性应答在记忆B细胞亚群中的分布。综上所述，我们的发现为HIV感染中病毒特异性B细胞反应提供了有价值的见解，并证明记忆B细胞异常可能导致感染个体的抗体反应无效。
Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. Despite extensive evidence of B cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, we used HIV envelope gp140 and CD4 or coreceptor (CoR) binding site (bs) mutant probes to evaluate HIV-specific responses in peripheral blood B cells of HIV-infected individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs, which is a poorly neutralizing epitope, arose early, whereas those against the well-characterized neutralizing epitope CD4bs were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. The distribution of HIV-specific responses among memory B cell subsets was corroborated by transcriptional analyses. Taken together, our findings provide valuable insight into virus-specific B cell responses in HIV infection and demonstrate that memory B cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals.