Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice.
Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice.
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DOI：
10.1038/ncomms10618
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发表时间：
2016-02-24
影响因子：
16.6
通讯作者：
Stamatatos L
中科院分区：
文献类型：
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作者：
McGuire AT;Gray MD;Dosenovic P;Gitlin AD;Freund NT;Petersen J;Correnti C;Johnsen W;Kegel R;Stuart AB;Glenn J;Seaman MS;Schief WR;Strong RK;Nussenzweig MC;Stamatatos L
VRC 01类广泛中和HIV-1抗体保护动物免受实验感染，并可能有助于有效的疫苗反应。它们的预测生殖系形式（gl）无效地结合Env，这可以解释为什么它们不被HIV-1 Env免疫诱导。在这里，我们表明优化的Env免疫原可以接合多种glVRC 01类抗体。此外，该免疫原在体内激活表达与内源性小鼠轻链配对的3BNC 60的人种系重链的幼稚B细胞。为了确定它是否激活表达完全人源化的gl 3BNC 60 B细胞受体（BCR）的B细胞，我们免疫了携带gl 3BNC 60的重链和轻链的小鼠。表达该BCR的B细胞显示自身反应性表型，并且不能有效地对优化的免疫原的可溶形式应答，除非其高度多聚化。因此，特别设计的Env免疫原可以激活表达对应于广泛中和HIV-1抗体前体的人BCR的幼稚B细胞，即使当B细胞显示自身反应性表型时。 广泛中和抗体（bNAb）的诱导是HIV-1疫苗研究的目标。在此，作者证明了HIV Env衍生的免疫原结合一类bNAb的生殖系前体并在敲入小鼠模型中激活相应的B细胞的能力
VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype. The induction of broadly neutralizing antibodies (bNAbs) is a goal of HIV-1 vaccine research. Here the authors demonstrate the ability of an HIV Env-derived immunogen to bind germline precursors of a class of bNAbs and to activate the corresponding B cells in a knock-in mouse model