Antibody Maturation Elicited by Integrase Defective Lentiviral Vectors

开发一种能够产生持久的和广泛反应的功能性抗体的HIV-1疫苗仍然是一项 悬而未决的问题。而介导抗体依赖性细胞毒作用的非中和抗体 (ADCC)更容易被当前的疫苗策略诱导，这些疫苗没有提供长期的 保护。诱导广谱中和抗体(BNAbs)的疫苗一直是该领域的目标，但已知 BNAbs的共同特征使它们不太可能被疫苗引发。最近的研究表明 可以通过使用B细胞系免疫原设计来选择性地诱导bNAbs-例如，通过利用 BNab成熟途径来源于HIV-1感染者。然而，在确实制造bNAbs的患者中，它 已有研究表明，bNAbs很少在感染后约2.5年前出现，这表明持久性抗原 驱动bNab开发可能需要驱动器。因此，提供持久抗原性的疫苗策略 使用精心挑选的免疫原进行刺激可能能够推动bNAbs的发展并改善 ADCC介导的抗体的持久性，可以提供保护免受感染。要问的问题是 该项目解决的问题是整合酶缺陷慢病毒载体对持续抗原的刺激作用 (IDLV)设计为顺序表达Ch505 T/F信封和一系列与 广泛的CD4结合位点中和抗体可诱导出具有抗HIV-1功能活性的抗体， 包括bNAbs和非中和抗体(V1V2、ADCC)。病毒式的挑战将决定这一战略是否 可以提供保护。我们假设持续的抗原刺激与B细胞系相结合 免疫基因设计将促进抗体成熟，从而发展出 已知的bNAbs，并将导致B细胞克隆谱系随着时间的推移而持续存在。AIM.1-确定功能 表达CH505envs的IDLV诱导的血浆抗体活性。AIM.2-确定B细胞的程度 表达CH505envs的IDLV诱导成熟和克隆扩增。AIM.3-确定 表达Ch505 envs的IDLV诱导的TFH反应。

The development of an HIV-1 vaccine that elicits durable and broadly reactive functional antibodies remains an unsolved problem. While non-neutralizing antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) are more readily induced by current vaccine strategies, these vaccines have not provided long-term protection. Vaccines that elicit broadly neutralizing antibodies (bnAbs) have been a goal for the field, but known bnAbs share characteristics that make them less likely to be elicited by vaccines. Recent work has suggested bnAbs may be selectively elicited through the use of B cell lineage immunogen design—eg, by harnessing bnAb maturation pathways derived from HIV-1 infected patients. However, in patients that do make bnAbs, it has been shown that bnAbs rarely arise before ~2.5 years after infection, suggesting that persistent antigen drive may be required to drive bnAb development. Thus, vaccine strategies that provide persistent antigenic stimulation using carefully selected immunogens may be able to drive the development of bnAbs and improve the durability of ADCC-mediating antibodies that could provide protection from infection. The question to be addressed by this project is whether persistent antigen stimulation by integrase-defective lentiviral vectors (IDLVs) engineered to sequentially express CH505 T/F envelope and a series of variants assoicated with broad CD4 binding site neutralizing antibodies can elicit antibodies with functional activities against HIV-1, including bnAbs and non-neutralizing antibodies (V1V2, ADCC). A viral challenge will determine if this strategy can provide protection. We hypothesize that persistent antigenic stimulation combined with B-cell lineage immunogen design will promote antibody maturation leading to the development of characteristics shared by known bnAbs and will result in the persistence of B cell clonal lineages over time. AIM.1—Determine functional plasma antibody activity elicited by IDLVs expressing CH505 Envs. AIM.2—Determine the degree of B cell maturation and clonal expansion elicited by IDLVs expressing CH505 Envs. AIM.3—Determine the degree of Tfh response elicited by IDLVs expressing CH505 Envs.