Detailed mapping and analysis of the evolution of neutralizing antibody responses

大多数慢性艾滋病毒感染者都经历了免疫系统的大规模失调。长寿记忆B细胞消失，而未成熟的B细胞过度激活，并产生大量无效的免疫球蛋白。此外，艾滋病毒的主要目标--CD4细胞在慢性感染阶段稳步下降。大约10%-20%的HIV感染者克服或逃脱了这种普遍的免疫功能障碍，并产生了广泛的HIV中和抗体。了解这些个体是如何产生针对艾滋病毒的广泛中和抗体的，对于艾滋病毒疫苗的开发至关重要。 我们假设，H1V+精英中和者与普通或中和能力差的人相比，B淋巴细胞室的破坏较少，和/或滤泡辅助CD4T淋巴细胞的数量增加。这一假设将通过在感染后的两个早期和两个晚期时间点对B和T淋巴细胞群体进行多参数流式细胞术分析来验证，比较产生广谱中和抗体的个体与中等/差中和剂和未感染的个体。B淋巴细胞分化为抗体分泌细胞的能力和滤泡T辅助细胞的能力 产生重要辅助细胞因子的CD4细胞，如IL-4和IL-21，也将在精英和中和能力差的人中进行比较。这些发现将有助于确定精英中和者如何产生有用的艾滋病毒抗体，并可能极大地帮助开发有效的艾滋病毒疫苗。

Most individuals with chronic HIV infection experience massive dysregulation of the immune system. Longlived memory B cells disappear, while immature B cells are hyperactivated and produce significant quantities of ineffective immunoglobulin. Furthermore, CD4 cells, the primary targets of HIV, steadily decline during the chronic phase of infection. Approximately 10-20% of HIV infected individuals overcome or escape this widespread immune dysfunction and produce broadly neutralizing antibodies to HIV. An understanding of how these indivduals generate broadly neutralizing antibodies to HIV is critical for HIV vaccine development. We hypothesize that H1V+ elite neutralizers have a less disrupted B lymphocyte compartment and/or an enhanced population of follicular helper CD4 T lymphocytes when compared to average or poorly neutralizing individuals. This hypothesis will be tested by multiparameter flow cytometric analysis of B and T lymphocyte populations at two early and two late time points post-infection, comparing indivuals who generate broadly neutralizing antibodies with average/poor neutralizers and uninfected individuals. The ability of B lymphocytes to differentiate into antibody secreting cells and the capacity of follicular T helper CD4 cells to produce important helper cytokines, such as IL-4 and IL-21, will also be compared in elite and poorly neutralizing individuals. These findings will help determine how elite neutralizers generate useful antibodies to HIV, and could greatly assist in the development of an effective HIV vaccine.