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Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model
Jasmine Samal, … , Aala Zakir, Moses Bility
Jasmine Samal, … , Aala Zakir, Moses Bility
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e120430. https://doi.org/10.1172/jci.insight.120430.
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Resource and Technical Advance AIDS/HIV

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

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Abstract

A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection–induced lymphoid tissue fibrosis on immunodeficiency and immune cell impairment is critical for therapeutics development and clinical translation. Said model will enable in vivo mechanistic studies, thus complementing the well-established surrogate model of SIV infection–induced lymphoid tissue fibrosis in macaques. We developed a potentially novel human immune system–humanized mouse model by coengrafting autologous fetal thymus, spleen, and liver organoids under the kidney capsule, along with i.v. injection of autologous fetal liver–derived hematopoietic stem cells, thus termed the BM-liver-thymus-spleen (BLTS) humanized mouse model. BLTS humanized mouse model supports development of human immune cells and human lymphoid organoids (human thymus and spleen organoids). HIV infection in BLTS humanized mice results in progressive fibrosis in human lymphoid tissues, which was associated with immunodeficiency in the lymphoid tissues, and lymphoid tissue fibrosis persists during ART, thus recapitulating clinical outcomes.

Authors

Jasmine Samal, Samantha Kelly, Ali Na-Shatal, Abdallah Elhakiem, Antu Das, Ming Ding, Anwesha Sanyal, Phalguni Gupta, Kevin Melody, Brad Roland, Watfa Ahmed, Aala Zakir, Moses Bility

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Figure 1

Construction of the BLTS humanized mouse model.

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Construction of the BLTS humanized mouse model.
In Step I, NSG mice are ...
In Step I, NSG mice are myoablated via γ irradiation (200 rads) using a Cesium-137 irradiator. In Step II, fetal tissues (spleen, thymus, and liver) are processed into 1 mm2 pieces and transplanted as a “sandwich” under the kidney capsule in irradiated NSG mice, following the administration of antibiotic and analogesic therapy and the induction of general anesthesia. In Step III, autologous CD34+ hematopoietic stem cells are isolated from the fetal liver via magnetic selection and transplanted at 2 × 105 cells per mouse via retro-orbital injection following kidney capsule transplantation of the lymphoid tissues. In Step IV, transplanted NSG mice were maintained under specific pathogen free conditions, and the human spleen and thymus organoids — along with other lymphoid tissues and associated immune cells — were allowed to develop over a period of 10 weeks, resulting in the BLTS humanized mouse model.

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