HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.
HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.
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DOI：
10.3389/fimmu.2022.1047277
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发表时间：
2022
影响因子：
7.3
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中科院分区：
文献类型：
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使用人源化小鼠作为HIV-1（HIV）感染模型的主要障碍是病毒特异性抗体应答的产生不足。人源化DRAGA（hDRAGA）小鼠产生抗原特异性类转换抗体的几种病原体，但他们是否这样做，在HIV感染和他们的次级淋巴组织（sLT）支持生发中心反应的程度是未知的。评估hDRAGA小鼠支持HIV复制、产生病毒特异性抗体应答、形成脾细胞亚群和组织sLT结构的能力。hDRAGA小鼠支持持续的HIV复制，并产生适度水平的gp 41特异性人IgM和IgG。未感染和HIV感染的hDRAGA小鼠的脾脏含有分化的B和CD 4 + T细胞亚群，包括生发中心（GC）B细胞和T滤泡辅助细胞（TFH）;与未感染的动物相比，HIV感染的hDRAGA小鼠中TFH和CD 8 + T细胞（但非GC B细胞）相对扩增。脾脏和肠系膜淋巴结切片的免疫荧光染色显示非典型形态。大多数CD 4+和CD 8 + T细胞位于CD 20 hi区域内。CD 20 hi区域缺乏典型的生发中心，如IgD-Ki 67+细胞染色所定义的。未检测到人滤泡树突状细胞（FDC）。小鼠FDC广泛分布于sLT的CD 20 hi和CD 20 lo区域。通过原位杂交检测到HIV RNA颗粒在CD 20+区域内，并且一些与小鼠FDC共定位。与sLT的CD 20 lo区域相比，病毒RNA+细胞在CD 20 hi区域内更集中，但当调整CD 4+细胞频率时，脾脏中的差异减小，肠系膜淋巴结中的差异消除。因此，hDRAGA小鼠重现了HIV发病机制的多个方面，包括HIV复制、TFH和CD 8 + T细胞的相对扩增以及适度的HIV特异性抗体产生。然而，在sLT中没有观察到经典的生发中心形态，这可能是该模型中GC B细胞扩增效率低下和产生低滴度的人抗HIV-1抗体应答的原因。
A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4+ T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8+ T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4+ and CD8+ T cells resided within CD20hi areas. CD20hi areas lacked canonical germinal centers, as defined by staining for IgD-Ki67+cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20hi and CD20lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20+ areas and some co-localized with mouse FDC. Viral RNA+ cells were more concentrated within CD20hi compared to CD20lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4+ cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8+ T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model.