Bhattarai Shaurav, Kadry Rana, Yeapuri Pravin, Lu Yaman, Foster Emma G, Zhang Chen, Dash Prasanta, Poluektova Larisa Y, Gorantla Santhi, Mosley R Lee, Gendelman Howard E
Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA.
NeuroImmune Pharm Ther. 2025 Feb 10;4(1):27-38. doi: 10.1515/nipt-2024-0018. eCollection 2025 Mar.
Amyloid-β (Aβ) plaque deposition in the brain is a principal pathological feature of both Alzheimer's disease (AD) and progressive human immunodeficiency virus type one (HIV-1) infection. Both enable Aβ assembly and Aβ protein aggregation. The potential link between HIV-1 and AD remains uncertain, supporting the need for a reliable animal model. HIV-1 is tropic and pathogenic for humans. It does not replicate in mice. The restricted species tropism has slowed progress in basic research activities. The current study seeks to correct animal model limitations.
We created an AD mouse to address the need to develop an small animal model that allows studies of viral infection by making a knock-in (KI) with the human amyloid precursor protein (APP) Swedish mutation to the mouse genome. The resulting founder mice were crossed with immunodeficient NOG (NOD. Cg- Tg(CMV)/Jic) to generate NOG/APP/IL-34 (NAIL) mice. The mice were reconstituted with human hematopoietic stem cells to generate NAIL mice with functional adaptive and innate human immune systems. Four-month-old, humanized NAIL mice were infected with HIV-1, a macrophage-tropic viral strain then evaluated for viral infection and AD pathology.
Productive HIV-1 infection was confirmed by plasma HIV-1 RNA levels in infected NAIL mice. The viral load increased by tenfold between day 10 and day 25 post-infection. By day 25, viral DNA confirmed the establishment of HIV-1 reservoirs in CD45+ cells from the immune tissues of infected NAIL mice. Additionally, p24 measurements in lymphoid and brain tissues of NAIL mice validated productive HIV-1 infection. Amyloid burden from infected NAIL mice was increased. Immunofluorescence staining revealed co-localization of Aβ fibrils and HLA-DR microglia in infected NAIL mice.
These results highlight the AD-HIV model's unique pathobiological and infectious features where the viral and immune responses can now be measured.
脑内淀粉样β（Aβ）斑块沉积是阿尔茨海默病（AD）和人类免疫缺陷病毒1型（HIV-1）进行性感染的主要病理特征。二者均可促使Aβ组装和Aβ蛋白聚集。HIV-1与AD之间的潜在联系仍不明确，这支持了建立可靠动物模型的必要性。HIV-1具有嗜人性且对人类致病。它在小鼠体内不复制。这种受限的物种嗜性减缓了基础研究活动的进展。当前研究旨在纠正动物模型的局限性。
我们通过将携带瑞典突变的人类淀粉样前体蛋白（APP）敲入（KI）小鼠基因组，创建了一种AD小鼠，以满足开发一种能够研究病毒感染的小动物模型的需求。将所得的奠基小鼠与免疫缺陷的NOG（NOD.Cg-Tg(CMV)/Jic）小鼠杂交，以生成NOG/APP/IL-34（NAIL）小鼠。用人类造血干细胞对这些小鼠进行重建，以生成具有功能性适应性和先天性人类免疫系统的NAIL小鼠。对4个月大的人源化NAIL小鼠感染HIV-1（一种巨噬细胞嗜性病毒株），然后评估病毒感染和AD病理情况。
通过检测感染的NAIL小鼠血浆中的HIV-1 RNA水平，证实了HIV-1的有效感染。感染后第10天至第25天，病毒载量增加了10倍。到第25天，病毒DNA证实HIV-1在感染的NAIL小鼠免疫组织的CD45+细胞中建立了病毒库。此外，对NAIL小鼠淋巴组织和脑组织中的p24检测证实了HIV-1的有效感染。感染的NAIL小鼠的淀粉样蛋白负荷增加。免疫荧光染色显示，在感染的NAIL小鼠中，Aβ纤维与HLA-DR小胶质细胞共定位。
这些结果突出了AD-HIV模型独特的病理生物学和感染特征，现在可以对病毒和免疫反应进行检测。
