Eliciting B cells to produce anti-HIV gp41 MPER-specific neutralizing antibodies

确定疫苗诱导的IHIV-I免疫的关键阶段 只有在细胞免疫应答抑制HIV复制后才出现中和血清抗体应答，这导致人们对体液免疫在控制HIV感染中的重要性产生怀疑。尽管如此，罕见的，广泛的交叉反应性抗体能够在体外中和多种HIV-1分离株，并且当被动给药时可以预防实验性感染。因此，有效的体液免疫应答对于开发保护性HIV-1疫苗仍然至关重要。 为什么艾滋病病毒感染者很少产生这种抗体？为什么HIV-1包膜上的中和表位免疫原性如此差？对HIV-1广泛反应性中和抗体的显著缺乏已经提供了几种解释，包括HIV包膜抗原的复杂性和遗传可塑性，通过糖基化屏蔽关键抗原位点，通过非中和表面抗原的竞争性抑制，免疫耐受性，以及初级抗体库的多样性不足。所有这些假设都是合理的，但尚未进行对HIV-1抗原的初级免疫应答的非常详细的原位研究。我们知道HIV-1中和 表位的免疫原性差，但我们不知道为什么。因此，我们将开展研究，通过关注细胞迁移、相互作用、增殖和分化的特征模式，确定HIV-1疫苗免疫小鼠体液应答的任何缺陷，这些特征模式是产生稳健有效抗体所必需的。我们的研究将使用组织学，流式细胞术和分子遗传学比较HIV-1和对照疫苗的反应，并将确定这些差异，可能占保护性HIV-1抗体的稀有性。

Identifying Critical Stages in Vaccine Induced IHIV-I Immunity The emergence of neutralizing serum antibody responses only after cellular immune responses have suppressed HIV replication has led to doubts regarding the importance of humoral immunity in controlling HIV infections. Nonetheless, rare, broadly cross-reactive antibodies are capable of neutralizing multiple isolates of HIV-1 in vitro, and when passively administered can prevent experimental infections. Thus, efficacious humoral immune responses remain crucial to the development of protective HIV-1 vaccines. Why are such antibodies rarely produced by HIV-infected patients? Why are the neutralizing epitopes present on the HIV-1 envelope so poorly immunogenic? Several explanations for the remarkable scarcity of HIV-1 broadly reactive, neutralizing antibody have been offered including the complexity and genetic plasticity of the HIV envelope antigens, the shielding of crucial antigen sites by glycosylation, competitive suppression by non-neutralizing surface antigens, immunological tolerance, and insufficient diversity in the primary antibody repertoire. All of these hypotheses are plausible, but remarkably detailed in situ studies of primary immune responses to HIV-1 antigens have not been performed. We know that HIV-1 neutralizing epitopes are poorly immunogenic but we do not know why. We shall, therefore, carry out studies to identify any deficits in the humoral responses of mice immunized with HIV-1 vaccines by focusing on the characteristic patterns of cellular migration, interaction, proliferation, and differentiation necessary for robust and efficacious antibody production. Our studies will use histologic, flow cytometric and molecular genetic comparisons of responses to HIV-1 and control vaccines and will identify those differences that may account for the rarity of protective HIV-1 antibody.