Long-lived plasma cells in HIV infection and vaccination

1背景/理由：这项资助的前提是，尽管抗体在免疫系统中具有潜在的重要性， 2预防和控制艾滋病病毒感染，缺乏持久的抗艾滋病病毒gp 120反应是一个问题 3.艾滋病毒疫苗的开发威胁到其潜在的效用。 4 5目的：我们的假设是，长寿浆细胞之间的定量和定性差异， 6，使抗HIV Env抗体相比，那些不。我们有最近的详细数据， 7例HIV感染者，我们从他们那里获得了详细的骨髓库数据， 8鉴定和分离循环中的主要抗体。知道哪些抗体构成 9库允许我们鉴定和追踪各种浆细胞区室中的抗体分泌细胞。 10这样做，我们已经确定了浆细胞，包括长寿的浆细胞，产生抗gp 120 11抗体确实可以在慢性HIV感染者的骨髓中找到。具体目标是 12项建议是：1）比较骨髓长寿命浆细胞分泌抗- 13种gp 120抗体与非gp 120长寿命浆细胞; 2）比较骨 14例骨髓长寿命浆细胞分泌抗gp 120抗体至非gp 120长寿命浆细胞; 3） 15确定cART治疗对骨髓中分泌抗Env抗体的浆细胞的影响。 16 17方法：我们计划研究来自几个不同人群的浆细胞：慢性HIV 18例感染者、接受cART的HIV感染者和接种过IHV 01 HIV疫苗的正常志愿者 19项研究。骨髓样本将根据CD 19和CD 138表达分为4个群体。的 第一步是确定抗gp 120、抗gp 41、抗p24和抗白喉骨髓库， 21名供体（6名cART前后慢性感染者和6名HIV疫苗接种供体）。此后，细胞签名 22（转录组）之间进行比较， 23个浆细胞亚群和队列。其次，表型差异（克隆频率，Elispot，分泌速率） 24将被测量，然后在组之间进行比较，如上所述。使用cART前后的配对样本 25治疗，我们将研究cART对浆细胞转录组和表型谱的影响。 26个子集。我们还将确定在HIV感染中观察到的抗gp 120长寿命浆细胞是否是“短暂的”。 27（cART消失），以及是否可以在HIV感染或疫苗接种中看到“真正的”长寿人群。 28 影响：我们建议上述研究将阐明抗体寿命缺陷的性质， 30 HIV-1 gp 120，这将对HIV疫苗设计产生直接影响。

1 Background/Rationale: The premise of this grant is that despite the potential importance of antibodies in the 2 prevention and control of HIV infection, the lack of durability in the anti-HIV gp120 response is a problem for 3 HIV vaccine development that threatens their potential utility. 4 5 Objectives: Our hypothesis is that quantitative and qualitative differences between the long-lived plasma cells 6 that make anti-HIV Env antibodies compared to those that do not. We have recent and detailed data from a 7 number of HIV-infected individuals from whom we have obtained detailed bone marrow repertoire data, 8 identifying and isolating the predominant antibodies in circulation. Knowing which antibodies constitute the 9 repertoire allows us to identify and track the antibody secreting cells in the various plasma cell compartments. 10 Doing this, we have identified that plasma cells, including long-lived plasma cells, that produce anti-gp120 11 antibody can indeed be found in the bone marrow patients with chronic HIV infection. The specific aims of this 12 proposal are 1) Compare the transcriptional profile of bone marrow long-lived plasma cells secreting anti- 13 gp120 antibodies to non-gp120 long-lived plasma cells; 2) Compare phenotypic differences between bone 14 marrow long-lived plasma cells secreting anti-gp120 antibodies to non-gp120 long-lived plasma cells; 3) 15 Determine the effect of cART treatment on anti-Env antibody secreting plasma cells in the bone marrow. 16 17 Methods: We plan on studying the plasma cells from several different groups of individuals: chronic HIV 18 infected, HIV-infected on cART, and normal volunteers who have been vaccinated in the IHV01 HIV vaccine 19 studies. Bone marrow samples will be sorted into four populations based on CD19 and CD138 expression. The 20 first step is to define the anti-gp120, anti-gp41, anti-p24, and anti-diphtheria bone marrow repertoire in the 21 donors (6 chronically infected pre and post-cART and 6 HIV vaccinee donors). Thereafter the cell signatures 22 (transcriptome) amongst the various antigen-specific plasma cells will be compared with each other, across 23 plasma cell subsets, and cohorts. Next, the phenotypic differences (clonal frequency, Elispot, secretion rates) 24 will be measured and then compared between groups, as above. Using paired samples before and after cART 25 therapy, we will study the effects of cART on the transcriptome and phenotypic profile of the plasma cell 26 subsets. We will also determine if the anti-gp120 long-lived plasma cells seen in HIV infection are “transient” 27 (disappear with cART), and whether a “true” long-lived population can be seen in HIV infection or vaccination. 28 29 Impact: We propose that the studies above will elucidate the nature of the antibody longevity defect against 30 HIV-1 gp120, which will have direct implications for HIV vaccine design.