Native-like Envelope Trimer Therapeutic Vaccination for Induction of Broadly Neutralizing Antibodies to Facilitate HIV Functional Cure

项目摘要 被动转移的广泛中和抗体（bnAb）正在HIV-1的临床试验中进行评估 治疗和预防。这些在猕猴和人类中的研究结果表明，bnAb具有 抗病毒活性和可能的“疫苗”效应，即诱导HIV特异性细胞免疫应答。后 感染数年后，大约5-15%的HIV-1感染者会发展出某种交叉感染能力， 中和广泛的异源病毒株，只有1%的个体开发出有效的bnAb。是 慢性HIV-1感染的个体可能引发了HIV bnAb的前体，但这些前体可能是HIV bnAb。 应答由于病毒逃逸或由于远离高度保守表位的亲和力成熟而受到阻碍。如果 正如我们的初步数据所表明的那样，HIV bnAb前体确实在这些个体中被诱导， 可以通过递送天然样HIV-1包膜（Env）三聚体来增强应答。治疗方法的发展 这将是HIV-1治疗和预防的一个有价值的进展。我们 使用对VRC 01类特别敏感的策展病毒板进行中和试验 前体抗体，V2顶点前体和PGT 121前体抗体，并证明基线 在慢性HIV 1感染者的一个小队列（N = 25）中，bnAb前体的频率约为20 因此，我们建议测试bnAb是否可以通过用天然抗逆转录病毒药物免疫诱导。 像Env三聚体疫苗在慢性，ART抑制HIV-1感染，包括在个人谁开始 通过自然感染的B细胞体细胞超变的适当途径。天然样三聚体模拟了 病毒表面上Env的结构在很大程度上是正确的，并以一种方式展示多个bnAb表位 类似于这些表位如何出现在病毒体相关刺突上，并且可以诱导自体原代病毒 因此，我们将进行1期、随机化、安慰剂对照， 探索性剂量递增研究，评价天然样三聚体疫苗VRC- HIVRGP 096 -00-VP（三聚体4571），由NIH疫苗研究中心开发并提供给我们，在HIV- 我们将评估疫苗诱导的自体和交叉免疫的变化。 进化枝病毒中和和三聚体特异性抗体应答。此外，我们还将详细 研究bnAb前体存在对bnAb B细胞谱系发育的影响的机制研究， 表征表位特异性并评估B细胞库中三聚体诱导的变化。使用多个， 最先进的检测方法，我们将测量免疫原对外周血HIV-1大小的影响 对残留血浆病毒血症和细胞HIV Env RNA的储存和潜在筛选作用。三聚体诱导 病毒学和免疫学评估将为这些疾病的条件和益处提供新的见解， 中和抗体应答，以实现持续的HIV-1缓解，而无需ART。

PROJECT SUMMARY Passively transferred broadly neutralizing antibodies (bnAbs) are being evaluated in clinical trials for HIV-1 treatment and prevention. The results of these studies in macaques and humans suggest that bnAbs have antiviral activity and possibly a “vaccinal” effect, i.e. induction of HIV-specific cellular immune responses. After several years of infection, approximately 5-15% of HIV-1 infected individuals develop some ability to cross- neutralize a broad range of heterologous viral strains, with only 1% of individuals developing potent bnAbs. It is possible that individuals with chronic HIV-1 infection have elicited precursors of HIV bnAbs, but that these responses have been stunted by viral escape or by affinity maturation away from highly conserved epitopes. If HIV bnAb precursors have indeed been elicited in these individuals as our preliminary data indicates, then such responses could be boosted by delivery of native-like HIV-1 envelope (Env) trimers. Development of therapies that may induce bnAb in vivo would be a valuable advance for both HIV-1 treatment and prevention. We conducted neutralization assays with curated virus panels that are particularly sensitive to VRC01-class precursor antibodies, V2 apex-precursors and PGT 121 precursor antibodies and demonstrated that the baseline frequencies of bnAb precursors was ~20% in a small cohort (N = 25) of chronically HIV 1-infected individuals receiving suppressive ART. We therefore propose to test if bnAbs can be induced by immunization with native- like Env trimer vaccination in chronic, ART-suppressed HIV-1 infection, including in individuals who have initiated the appropriate pathways of B-cell somatic hypermutation through natural infection. Native-like trimers mimic the structure of Env on the surface of the virus largely correctly and display multiple bnAb epitopes in a manner similar to how these epitopes appear on the virion-associated spike, and can induce autologous primary virus (Tier-2) responses in animal models .Accordingly, we will conduct a Phase 1, randomized, placebo controlled, exploratory dose-escalation study evaluating the safety and immunogenicity of a native-like trimer vaccine, VRC- HIVRGP096-00-VP (Trimer 4571), developed and provided to us by the NIH Vaccine Research Center, in HIV- 1 infected individuals on suppressive ART. We will assess vaccine induced changes in autologous and cross clade virus neutralization and trimer-specific antibody response. Additionally, we will perform detailed mechanistic studies to investigate the effect of bnAb precursor presence on bnAb B-cell lineage development, characterize epitope specificities and assess trimer-induced changes in the B cell repertoire. Using multiple, state-of-the-art assays, we will measure the effect of the immunogen on the size of the peripheral blood HIV-1 reservoir and potential sieving effect on the residual plasma viremia and cellular HIV Env RNA. Trimer induced virologic and immunological assessments will provide new insights into the conditions and the benefits of these neutralizing antibody responses toward achieving sustained HIV-1 remission without ART.