The Role of Follicular Helper T Cells in HIV Prime Boost Vaccination

描述：预防人类免疫缺陷病毒1型(HIV-1)传播的一个主要目标是开发一种具有广泛保护性的疫苗。然而，由于HIV-1的极端遗传多样性和HIV-1环境抗原的免疫原性很差，这一目标一直难以实现。有效保护性HIV-1疫苗的一个关键因素是广谱中和抗体(BNAbs)，它可以阻止不同组的初级HIV-1病毒分离株的感染。 虽然已经从艾滋病毒感染者身上发现了bNAbs，但如何通过疫苗接种来诱导bNAbs的问题仍然存在。最近，异源Prib-Boost方法已成为诱导免疫保护和高质量抗体应答的一种有前景的策略。该方法首先由基于基因的疫苗(以病毒载体或DNA质粒的形式)进行抗原启动，然后以重组蛋白的形式增加匹配的Ag。我们以前的研究已经建立了一个以HIV gp120为抗原的Prime-Boost系统，当抗原通过DNA Prime-Protein Boost方法以多价形式递送时，能够在人类中诱导bNAbs。通常情况下，bNAbs是广泛的B细胞克隆选择和进化的产物，并表现出高度的体细胞超突变。因此，诱导bNAbs需要很强的生发中心(GC)反应。因为GC反应依赖于特殊的滤泡辅助T细胞(TFH细胞)，所以我们调查了初级加强免疫是否影响TFH细胞的发育。我们的初步工作表明，与单独的蛋白质免疫相比，DNA免疫和蛋白质免疫促进了TFH细胞的发育，极大地促进了GC的发育，并提高了抗体效价和功能亲和力。然而，在HIV-1疫苗环境中控制TFH发展和活性的详细免疫学机制是完全未知的。我们提出的假设是：1)与蛋白质启动相比，gp120 DNA启动可诱导更好的TFH细胞反应；2)启动和增强免疫对影响TFH细胞和生发中心反应的仔细协调是在启动-增强过程结束时产生抗gp120特异性抗体的关键；以及3)更强的TFH反应与在小鼠和人类中可检测到的循环“TFH细胞”相关。在目前的方案中，我们将研究DNA启动诱导TFH细胞的机制，以及这如何允许宿主在加强疫苗接种后产生高水平的抗体反应。我们的最终目标是利用这一知识促进高效艾滋病毒疫苗的开发。

DESCRIPTION: A major goal towards preventing the transmission of Human Immunodeficiency Virus type-1 (HIV-1) is the development of a broadly protective vaccine. However, this goal has been elusive due to the extreme genetic diversity of HIV-1 and poor immunogenicity of HIV-1 Env antigens. One key element of an effective protective HIV-1 vaccine is broadly neutralizing antibodies (bnAbs) that can block the infection of a diverse group of primary HIV-1 viral isolates. While bnAbs have been identified from HIV-infected patients, the problem of how to induce bnAbs through vaccination has persisted. Lately, the heterologous prime-boost approach, where the initial antigenic priming is given by a gene-based vaccine (in the form of viral vector or DNA plasmid), followed by a boost of matching Ag in the form of recombinant protein, has become a promising strategy to elicit immune protection and high quality antibody responses. Our previous research has established that a prime-boost system with HIV gp120 as the Ag is capable of inducing bnAbs in humans when the antigens were delivered as a polyvalent formulation by the DNA prime-protein boost approach. Typically, bnAbs are the product of extensive B cell clonal selection and evolution, and display a high degree of somatic hypermutation. Thus, inducing bnAbs requires a strong germinal center (GC) reaction. Because the GC reaction is dependent upon specialized follicular helper T cells (TFH cells), we investigated whether prime-boost vaccination affected the development of TFH cells. Our preliminary work revealed that DNA priming followed by protein boosting led to augmented TFH cell development, greatly enhanced GC development, and higher Ab titers and functional affinity, compared to protein immunization alone. However, the detailed immunological mechanisms controlling TFH development and activity in an HIV-1 vaccine setting are completely unknown. We have developed the hypothesis that 1) compared to protein priming, gp120 DNA priming induces a better TFH cell response, 2) careful coordination of priming and boosting immunizations affecting TFH cells and the germinal center response is crucial for the development of anti-gp120-specific antibodies at the end of prime-boost process, and 3) a stronger TFH response correlates with detectable circulating "blood-TFH cells" in both mice and humans. In the current proposal, we will investigate the mechanisms by which DNA priming induces TFH cells, and how this allows the host to produce high-level Ab responses following booster vaccinations. Our ultimate goal is to use this knowledge to foster the development of a highly effective HIV vaccine.