Kumar Rajnish, Visciano Maria Luisa, Li Hualin, Hioe Catarina
New York University School of Medicine, Department of Pathology, New York, NY 10016, USA.
J AIDS Clin Res. 2012 Mar 9;S8(2). doi: 10.4172/2155-6113.S8-002.
There are formidable challenges in developing HIV vaccines that elicit potent neutralizing antibodies against a broad array of HIV-1 isolates. The key targets for these neutralizing antibodies are the viral envelope antigens gp120 and gp41. Although broadly reactive neutralizing epitopes on gp120 and gp41 have been mapped and studied extensively, these epitopes are poorly immunogenic. Indeed, various vaccine candidates tested in preclinical and clinical trials do not generate antibodies against these epitopes. Hence, novel immunogen designs to augment the immunogenicity of these neutralizing epitopes are wanted. In this review, a unique immunogen design strategy that exploits immune complexes of gp120 and selected anti-gp120 monoclonal antibodies (mAb) to elicit neutralizing antibodies against cross-reactive V3 epitopes is discussed. The ability of these complexes to stimulate neutralizing antibodies is dictated by fine specificity and affinity of mAbs used to form the complexes, indicating the contribution of Fab-mediated activity, rather than conventional Fc-mediated enhancement. Further improvement of V3 immunogenicity is attainable by forming immune complexes with gp120 mutants lacking site-specific N-linked glycans. The increased V3 immunogenicity on the mutated gp120/mAb complexes correlates with enhancement of in vitro antibody recognition (antigenicity) and proteolytic resistance of V3 epitopes when presented on the complexes. These insights should provide guidelines for the development of more potent immunogens that target not only the prototypic V3 epitopes but also other broadly reactive epitopes on the HIV envelope.
开发能够引发针对多种HIV-1分离株的强效中和抗体的HIV疫苗面临着巨大挑战。这些中和抗体的关键靶点是病毒包膜抗原gp120和gp41。尽管gp120和gp41上具有广泛反应性的中和表位已被定位并广泛研究，但这些表位的免疫原性很差。事实上，在临床前和临床试验中测试的各种候选疫苗都不能产生针对这些表位的抗体。因此，需要新颖的免疫原设计来增强这些中和表位的免疫原性。在这篇综述中，讨论了一种独特的免疫原设计策略，该策略利用gp120与选定的抗gp120单克隆抗体（mAb）的免疫复合物来引发针对交叉反应性V3表位的中和抗体。这些复合物刺激中和抗体的能力取决于用于形成复合物的单克隆抗体的精细特异性和亲和力，这表明Fab介导的活性而非传统的Fc介导的增强作用起了作用。通过与缺乏位点特异性N-连接聚糖的gp120突变体形成免疫复合物，可以进一步提高V3的免疫原性。突变型gp120/单克隆抗体复合物上V3免疫原性的增加与复合物上呈现时V3表位的体外抗体识别（抗原性）增强和蛋白水解抗性相关。这些见解应为开发更有效的免疫原提供指导，这些免疫原不仅针对原型V3表位，还针对HIV包膜上其他具有广泛反应性的表位。
