Passive transfer of broadly neutralizing anti–HIV-1 antibodies (bNAbs) protects against infection, and therefore, eliciting bNAbs by vaccination is a major goal of HIV-1 vaccine efforts. bNAbs that target the CD4 binding site (CD4bs) on HIV-1 Env are among the most broadly active, but to date, responses elicited against this epitope in vaccinated animals have lacked potency and breadth. We hypothesized that CD4bs bNAbs resembling the antibody IOMA might be easier to elicit than other CD4bs antibodies that exhibit higher somatic mutation rates, a difficult-to-achieve mechanism to accommodate Env’s N276 gp120 N-glycan, and rare five-residue light chain complementarity-determining region 3. As an initial test of this idea, we developed IOMA germline–targeting Env immunogens and evaluated a sequential immunization regimen in transgenic mice expressing germline-reverted IOMA. These mice developed CD4bs epitope–specific responses with heterologous neutralization, and cloned antibodies overcame neutralization roadblocks, including accommodating the N276 gp120 glycan, with some neutralizing selected HIV-1 strains more potently than IOMA. The immunization regimen also elicited CD4bs-specific responses in mice containing polyclonal antibody repertoires as well as rabbits and rhesus macaques. Thus, germline targeting of IOMA-class antibody precursors represents a potential vaccine strategy to induce CD4bs bNAbs.

中文翻译：

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CD4 结合位点免疫原在转基因和野生型动物中引发异源抗 HIV-1 中和抗体

广泛中和抗 HIV-1 抗体 (bNAb) 的被动转移可防止感染，因此，通过疫苗接种引发 bNAb 是 HIV-1 疫苗工作的主要目标。靶向 HIV-1 Env 上的 CD4 结合位点 (CD4bs) 的 bNAb 是最广泛活跃的，但迄今为止，在接种疫苗的动物中针对该表位引起的反应缺乏效力和广度。我们假设类似于抗体 IOMA 的 CD4bs bNAbs 可能比其他表现出更高体细胞突变率的 CD4bs 抗体更容易引发，这是一种难以实现的机制来适应 Env 的 N276GP120N-聚糖和稀有的五残基轻链互补决定区 3。作为对这一想法的初步测试，我们开发了 IOMA 种系靶向 Env 免疫原，并评估了表达种系回复 IOMA 的转基因小鼠的序贯免疫方案。这些小鼠通过异源中和产生了 CD4bs 表位特异性反应，克隆抗体克服了中和障碍，包括适应 N276GP120聚糖，其中一些比 IOMA 更有效地中和选定的 HIV-1 菌株。免疫方案还在含有多克隆抗体库的小鼠以及兔子和恒河猴中引起 CD4bs 特异性反应。因此，IOMA 类抗体前体的种系靶向代表了诱导 CD4bs bNAbs 的潜在疫苗策略。