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

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

doi:10.1172/jci.insight.120430

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.

Highlights

The hallmark of chronic HIV infection is the depletion of CD4+ T cells, via direct virus-mediated killing and indirect killing, which leads to AIDS in the absence of antiretroviral therapy (ART)
Understanding the mechanisms of HIV-induced lymphoid tissue fibrosis and its role in chronic inflammation, immune cell impairment, immunodeficiency, and the generation, trafficking, and function of anti-HIV immune cells is critical for developing novel therapeutic strategies for treating persistent immune abnormalities associated with non-AIDS pathologies and eradicating the HIV reservoir; the BLTS humanized mouse model provides a platform for addressing these questions
Lymphoid tissue fibrosis is a major pathogenic feature associated with chronic HIV infection with or without ART; the mechanisms of HIV-induced lymphoid tissue fibrosis remains to be fully elucidated [7, 8]

Summary

Introduction

The hallmark of chronic HIV infection is the depletion of CD4+ T cells, via direct virus-mediated killing and indirect killing, which leads to AIDS in the absence of antiretroviral therapy (ART). Inflammatory response is a hallmark of chronic HIV infection, and studies suggest that HIV-induced inflammatory response results in lymphoid tissue fibrosis, which contributes to lymphoid tissue damage, CD4+ T cell depletion, and impaired CD4+ T cell reconstitution following ART [1,2,3,4,5,6,7]. Immune cells/therapeutic vaccine–based therapies for sustained HIV remission or eradication is predicated on the notion that infused or vaccine-induced immune cells will control or eradicate the HIV reservoir, which includes the HIV reservoir located in lymphoid tissues [9]. This idea posits that infused or vaccine-induced HIV–targeting immune cells will survive and maintain functionality in the fibrotic lymphoid tissues; there are no current small animal models for HIV-induced lymphoid tissue fibrosis to evaluate said notion

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Conclusion