STM：灵长类动物是研究HIV疫苗B细胞反应的模型

7月11日，Sci Transl Med杂志报道认为，为了研发更有效的HIV疫苗，我们应当应用灵长类动物对疫苗引发的B细胞反应进行更细微的研究。

人类和猕猴之间的整体基因同源性高，再加上淋巴细胞种群在表型上的保守性，使得非人灵长类动物（NHPs）在候选疫苗的临床前评价方面具有很大的潜在用途。

对于HIV-1，我们需要实验模型，以确定疫苗疗法是否能够引出所需的免疫反应，如产生广谱性的中和抗体（bNAbs）。一个重要的HIV-1包膜糖蛋白（ENVs）中和靶点是，保守的主要CD4受体结合位点（CD4bs）。

从HIV-1感染者体内，分离和鉴定CD4bs特异性中和单克隆抗体（mAbsc）有助于了解具有广泛反应活性的抗体如何靶向这一保守的抗原表位。相比之下，由于尚不理解的原因，当前使用的HIV-1包膜糖蛋白免疫原引起的CD4bs靶向抗体中和反应的广度非常有限。

为了促进使用的NHP模型来解决这个问题以及与人类体液免疫有关的其他问题，研究者确定了恒河猴免疫球蛋白（Ig）基因位点，并将其功能与人体免疫球蛋白位点相比。

然后，科学家又研究Env-免疫的恒河猴，确定表达CD4bs特异抗体的单个B细胞，还对功能性单克隆抗体进行了测序和表达。在比较疫苗引起的和HIV-1感染引起的单克隆抗体之后，科学家发现，在抗体突变的程度和靶向CD4bs的细微特异性上，两者存在着差异。

这些数据说明，我们应使用临床前NHP模型，对疫苗诱导的B细胞反应的特点进行更加深入细致的研究。

doi:10.1016/j.cell.2011.10.017
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High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site

Christopher Sundling1,*,Yuxing Li2,*,Nick Huynh1,Christian Poulsen2,Richard Wilson2,Sijy O’Dell3,Yu Feng2,John R. Mascola3,Richard T. Wyatt2,? andGunilla B. Karlsson Hedestam

The high overall genetic homology between humans and rhesus macaques, coupled with the phenotypic conservation of lymphocyte populations, highlights the potential use of nonhuman primates (NHPs) for the preclinical evaluation of vaccine candidates. For HIV-1, experimental models are needed to identify vaccine regimens capable of eliciting desired immune responses, such as broadly neutralizing antibodies (bNAbs). One important neutralization target on the HIV-1 envelope glycoproteins (Envs) is the conserved primary CD4 receptor binding site (CD4bs). The isolation and characterization of CD4bs-specific neutralizing monoclonal Abs (mAbs) from HIV-1–infected individuals have provided insights into how broadly reactive Abs target this conserved epitope. In contrast, and for reasons that are not understood, current Env immunogens elicit CD4bs-directed Abs with limited neutralization breadth. To facilitate the use of the NHP model to address this and other questions relevant to human humoral immunity, we defined features of the rhesus macaque immunoglobulin (Ig) loci and compared these to the human Ig loci. We then studied Env-immunized rhesus macaques, identified single B cells expressing CD4bs-specific Abs, and sequenced and expressed a panel of functional mAbs. Comparison of vaccine-elicited mAbs with HIV-1 infection–induced mAbs revealed differences in the degree of somatic hypermutation of the Abs as well as in the fine specificities targeted within the CD4bs. These data support the use of the preclinical NHP model to characterize vaccine-induced B cell responses at high resolution.