HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages
HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages
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DOI：
10.1128/jvi.00426-12
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发表时间：
2012-07-01
影响因子：
5.4
通讯作者：
Haynes, Barton F.
中科院分区：
文献类型：
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作者：
Moody, M. Anthony;Yates, Nicole L.;Haynes, Barton F.
大多数广泛中和HIV-1的抗体在抗体克隆谱系中高度体细胞突变，并随着时间的推移而存在。在这里，我们描述了在一项HIV-1疫苗试验(GSK PRO HIV-002)中诱导的人类抗体的分析，该试验使用克隆W6.1D(gp120(w6.ID))的分支B包膜(Env)gp120。采用双色抗原特异性分选方法，分离纯化了针对HIV-1Env的人源单抗，并对其在HIV-1Env疫苗接种中的克隆持久性进行了研究。我们发现了疫苗诱导的V-H体细胞突变的证据，但仅限于温和的水平(3.8%+/-0.5%；范围0-8.2%)。对在四次免疫中恢复的34株HIV-1反应性单抗的分析显示，有证据表明，幼稚B细胞的顺序招募和先前招募的记忆B细胞的重新刺激。这些重组抗体概括了参与者血清的抗HIV-1活性，包括假病毒中和和抗体依赖的细胞介导的细胞毒作用(ADCC)。一种抗体(3491)在体细胞突变后表现出特异性的变化，推测的未突变的祖先与线性C2肽结合，而突变的抗体仅与gp120 Env的构象表位反应。因此，gp120(w6.ID)具有很强的免疫原性，但超过四次免疫诱导的亲和力成熟水平低于广谱中和单抗。需要改进的疫苗接种策略来推动抗体克隆谱系的持续刺激，以诱导亲和力成熟，从而产生高度突变的HIV-1Env反应性抗体。
Most antibodies that broadly neutralize HIV-1 are highly somatically mutated in antibody clonal lineages that persist over time. Here, we describe the analysis of human antibodies induced during an HIV-1 vaccine trial (GSK PRO HIV-002) that used the clade B envelope (Env) gp120 of clone W6.1D (gp120(w6.ID)). Using dual-color antigen-specific sorting, we isolated Env-specific human monoclonal antibodies (MAbs) and studied the clonal persistence of antibodies in the setting of HIV-1 Env vaccination. We found evidence of V-H somatic mutation induced by the vaccine but only to a modest level (3.8% +/- 0.5%; range 0 to 8.2%). Analysis of 34 HIV-1-reactive MAbs recovered over four immunizations revealed evidence of both sequential recruitment of naive B cells and restimulation of previously recruited memory B cells. These recombinant antibodies recapitulated the anti-HIV-1 activity of participant serum including pseudovirus neutralization and antibody-dependent cell-mediated cytotoxicity (ADCC). One antibody (3491) demonstrated a change in specificity following somatic mutation with binding of the inferred unmutated ancestor to a linear C2 peptide while the mutated antibody reacted only with a conformational epitope in gp120 Env. Thus, gp120(w6.ID) was strongly immunogenic but over four immunizations induced levels of affinity maturation below that of broadly neutralizing MAbs. Improved vaccination strategies will be needed to drive persistent stimulation of antibody clonal lineages to induce affinity maturation that results in highly mutated HIV-1 Env-reactive antibodies.