Kardava Lela, Moir Susan, Shah Naisha, Wang Wei, Wilson Richard, Buckner Clarisa M, Santich Brian H, Kim Leo J Y, Spurlin Emily E, Nelson Amy K, Wheatley Adam K, Harvey Christopher J, McDermott Adrian B, Wucherpfennig Kai W, Chun Tae-Wook, Tsang John S, Li Yuxing, Fauci Anthony S
J Clin Invest. 2014 Jul;124(7):3252-62. doi: 10.1172/JCI74351. Epub 2014 Jun 2.
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.
最近，从HIV感染个体的记忆B细胞中分离出了几种中和性抗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，但对于这些罕见的HIV特异性抗体所源自的细胞却知之甚少。因此，我们使用HIV包膜糖蛋白140以及CD4或共受体（CoR）结合位点（bs）突变探针，来评估处于感染不同阶段的HIV感染个体外周血B细胞中的HIV特异性反应。与非HIV反应不同，针对糖蛋白140的HIV特异性反应在异常B细胞中富集，即活化和耗竭的记忆亚群，而这些细胞在未感染个体的血液中基本不存在。针对共受体结合位点（一种中和性较差的表位）的反应出现较早，而针对特征明确的中和性表位CD4结合位点的反应则延迟且不常见。在静止记忆B细胞（未感染个体中的主要亚群）中，HIV特异性反应的富集确实发生在某些感染个体中，这些个体无论是否接受抗逆转录病毒治疗，血浆病毒血症和免疫激活水平都较低。转录分析证实了HIV特异性反应在记忆B细胞亚群中的分布情况。综上所述，我们的研究结果为HIV感染中病毒特异性B细胞反应提供了有价值的见解，并表明记忆B细胞异常可能导致感染个体抗体反应无效。
