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

项目总结 被动转移的广谱中和抗体(BNAbs)正在HIV-1的临床试验中进行评估 治疗和预防。这些对猕猴和人类的研究结果表明，bNAbs具有 抗病毒活性和可能的“疫苗”效应，即诱导艾滋病毒特异性细胞免疫反应。之后 经过几年的感染，大约5%-15%的HIV-1感染者具有一定的交叉感染能力 中和广泛的异源病毒株，只有1%的人产生有效的bNAbs。它是 慢性HIV-1感染者可能诱发了HIV bNAbs的前体，但这些 由于病毒逃逸或高度保守表位的亲和力成熟，反应受阻。如果 正如我们的初步数据显示的那样，确实在这些人中诱导出了艾滋病毒bNab前体，然后 通过提供类似于本地的HIV-1包膜(Env)三聚体，可以增强应答。治疗方法的发展 这可能在体内诱导bNab，这对HIV-1的治疗和预防都是一个有价值的进步。我们 使用对VRC01类特别敏感的经过管理的病毒面板进行中和测试 前体抗体、V2顶点前体和PGT 121前体抗体并证明基线 在一小群(N=25)慢性HIV1感染者中，bNab前体的频率约为20% 接受压抑的艺术。因此，我们建议测试是否可以通过免疫原生生物诱导bNAbs。 就像在慢性、ART抑制的艾滋病毒-1感染中接种Env三聚体疫苗一样，包括在 自然感染引起B细胞体细胞超突变的适宜途径。类似本地的三聚体模仿了 病毒表面的包膜结构基本正确，并以一种方式显示了多个bNab表位 类似于这些表位出现在病毒粒子相关的尖峰上，并可以诱导自体原始病毒 动物模型的(Tier-2)反应。因此，我们将进行阶段1，随机，安慰剂对照， 一项评估国产三聚体疫苗VRC的安全性和免疫原性的探索性剂量递增研究 HIVRGP096-00-VP(Trimer 4571)，由美国国立卫生研究院疫苗研究中心开发并提供给我们，在HIV- 1个感染了抑制性艺术的人。我们将评估疫苗诱导的自体和交叉变化 分支病毒中和和三聚体特异性抗体反应。此外，我们还将执行详细的 研究bNab前体存在对bNab B细胞系发育的影响的机制研究， 鉴定抗原表位的特异性并评估三聚体引起的B细胞谱的变化。使用多个， 最先进的检测方法，我们将测量免疫原对外周血液HIV-1大小的影响 储存和潜在筛选对残留血浆病毒血症和细胞HIV env RNA的影响。三聚体诱导 病毒学和免疫学评估将为了解这些疾病的情况和益处提供新的见解 中和抗体反应以实现持续的HIV-1缓解，而不需要抗逆转录病毒治疗。

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.