Strategies for inducing bnAbs against QNES by infection with SHIVs

人类免疫缺陷不同分离株广谱中和抗体(BNAb)的诱导 在艾滋病疫苗研究中，病毒(HIV)仍然是一个未实现的目标。了解表位的性质 因此，由bNAb识别的抗体和产生这种抗体的机制至关重要。 重要性。L·莫里斯博士在南非的实验室最近的研究确定了一名患者的血清 (CAP256)，他对C亚型分离株具有强大的和广谱的中和活性。钥匙 这种反应性的决定因素映射到V1V2区域，并可能由高度不连续或 第四纪构造。类似的结构可能是新型单抗(Mab)的靶点。 以几个基团为特征，这些基团也具有非常强的中和活性。总的目标是 这项建议是为了建立猕猴模型来研究bNAb对 第四纪中和表位(QNE)以及导致这些抗体产生的因素。我们 假设在表达QNE的复制病毒感染的背景下抗原刺激有利于 针对这些表位的反应的产生，以及通过病毒的重复感染而重复暴露 这些表位的相关形式加强了这些反应：为了检验这些假设，我们建议 使现有的嵌合猴-人类免疫缺陷病毒(SHIV)表达V1V2决定簇 并检测其在猕猴体内的感染性和致病性。这样的可获得性 模型将允许我们比较表达各种形式的QNEs的病毒的免疫原性，并 分离出针对这些表位的单抗。本项目的具体目标是：(1)确定体内的 携带CAP256 QNE的嵌合SHV及其相关分离株的感染性和免疫原性； 检测不同QNE嵌合体的重叠感染，作为增强bNAb反应的一种方法； 以及(3)研究产生差异反应的动物的包膜序列的进化 抗新城疫病毒感染后的QNE。这些研究的结果将为进一步了解 针对HIV-1的bNAb反应及产生这种反应的新型免疫原的设计

Induction of broadly neutralizing antibodies (bNAb) against diverse isolates of human immunodeficiency virus (HIV) remains an unmet goal in AIDS vaccines research. Understanding the nature of the epitopes recognized by bNAb and the mechanisms by which such antibodies are generated are therefore of critical importance. Recent studies from Dr. L. Morris' lab in South Africa have identified a serum from a patient (CAP256), who possesses potent and broadly-reactive neutralizing activities for subtype C isolates. The key determinant of this reactivity maps to the V1V2 region and is likely to consist of highly discontinuous or quaternary structures. Similar structures may be targeted by novel monoclonal antibodies (MAb) characterized by several groups that also possess very potent neutralizing activities. The overall objective of this proposal is to develop macaque models to study the nature of the bNAb responses against the quaternary neutralizing epitopes (QNE) and factors that contribute to the generation of these antibodies. We hypothesize that antigenic stimulation in the context of infection by a replicating virus expressing QNE favors the generation of responses against these epitopes, and that repeated exposure by superinfection by viruses bearing related forms of such epitopes reinforces these responses: To test these hypotheses, we propose to adapt existing chimeric simian-human immunodeficiency viruses (SHIVs) to express the V1V2 determinants of conserved QNEs and to test their infectivity and pathogenicity in macaques. The availability of such models would allow us to compare the immunogenicity of viruses expressing various forms of QNEs and to isolate Mab specific for these epitopes. The Specific Aims of this Project are: (1) To determine the in vivo infectivity and immunogenicity of chimeric SHIV bearing the QNE of CAP256 and related isolates; (2) To examine superinfection by different QNE-bearing chimeras as an approach to enhance bNAb responses; and (3) To examine the evolution of envelope sequences in animals that develop differential responses against the QNE after SHIV infection. Results from these studies will provide further insight on the nature of the bNAb responses against HIV-1 and the design of novel immunogens to generate such responses