Antibody Maturation Elicited by Integrase Defective Lentiviral Vectors

开发一种能激发持久和广泛反应性功能抗体的HIV-1疫苗仍然是一个挑战。 未解决的问题而介导抗体依赖性细胞毒性的非中和抗体 （ADCC）更容易由当前的疫苗策略诱导，这些疫苗没有提供长期的免疫应答。 保护引发广泛中和抗体（bnAb）的疫苗一直是该领域的目标，但已知的是， bnAb具有使它们不太可能被疫苗引发的共同特征。最近的研究表明 bnAb可以通过使用B细胞谱系免疫原设计来选择性地引发，例如，通过利用 来自HIV-1感染患者的bnAb成熟途径。然而，在产生bnAb的患者中， 已经表明bnAb很少在感染后约2.5年前出现，这表明持续性抗原 可能需要驱动器来驱动bnAb开发。因此，提供持久抗原性的疫苗策略 使用精心选择的免疫原刺激可能能够驱动bnAb的发展，并提高免疫原性。 ADCC介导的抗体的持久性，可以提供保护免受感染。该问题 本项目的目的是研究整合酶缺陷型慢病毒载体是否能持续刺激抗原 （IDLV）被工程化以顺序表达CH 505 T/F包膜和一系列与T/F包膜相关的变体。 宽CD 4结合位点中和抗体可以引发具有抗HIV-1功能活性的抗体， 包括bnAb和非中和抗体（V1 V2，ADCC）。病毒挑战将决定这种策略 可以提供保护。我们假设持续的抗原刺激结合B细胞谱系 免疫原设计将促进抗体成熟，导致以下特征的发展： 已知的bnAb，并将导致B细胞克隆谱系随时间的持续。目标1-确定功能 由表达CH 505 Envs.目标2-确定B细胞的程度 通过表达CH 505 Envs的IDLV引起的成熟和克隆扩增。目标3-确定 由表达CH 505 Envs的IDLV引起的Tfh应答。

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.