Humanized mice for HIV and AIDS research

García, J. Víctor

doi:10.1016/j.coviro.2016.06.010

Cited by 58 publications

(44 citation statements)

References 93 publications

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“…thymus organoid (primary lymphoid organ), broadly termed human immune system-humanized mice, has been widely used to study HIV transmission, immunopathogenesis, chronic inflammation, and immune response and is highly amendable to mechanistic studies, thus providing a robust small animal model that complements the surrogate SIV macaque model (12). In human immune system-humanized mouse models, the immunodeficient mouse spleen is reconstituted with human immune cells to generate a humanized murine spleen; however, human immune cell reconstitution and associated red pulp and lymphoid follicle development in the humanized murine spleen is not optimal (13).…”

Section: Introductionmentioning

confidence: 99%

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

Samal¹,

Kelly²,

Na-Shatal³

et al. 2018

JCI Insight

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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.

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Section: Introductionmentioning

confidence: 99%

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

Samal¹,

Kelly²,

Na-Shatal³

et al. 2018

JCI Insight

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“…HIS mice have been intensively used to investigate the HIV-1 infectious cycle in vivo and immune responses [317]. However, very limited studies have employed these systems to evaluate the efficacy and safety of attenuation strategies for HIV-1.…”

Section: Assessing Lav Replication Fitness and Safety In His Micementioning

confidence: 99%

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

O'Connell

Douam

2020

Vaccines

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Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, such as the smallpox vaccine, the measles vaccine, and the yellow fever vaccine, have been isolated and/or developed in a purely empirical manner without any understanding of the immunological mechanisms they trigger. Today, the mechanisms governing potent LAV immunogenicity and long-term induced protective immunity continue to be elusive, and therefore hamper the rational design of innovative vaccine strategies. A serious roadblock to understanding LAV-induced immunity has been the lack of suitable and cost-effective animal models that can accurately mimic human immune responses. In the last two decades, human-immune system mice (HIS mice), i.e., mice engrafted with components of the human immune system, have been instrumental in investigating the life-cycle and immune responses to multiple human-tropic pathogens. However, their use in LAV research has remained limited. Here, we discuss the strong potential of LAVs as tools to enhance our understanding of human immunity and review the past, current and future contributions of HIS mice to this endeavor.

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“…those reconstituted with human immune systems (reviewed in (Victor Garcia, 2016)(Garcia blanco)), of which perhaps the best characterized and most advanced version is the BLT ( B one marrow- L iver- T hymus) model, i.e. Rag2 −/− γc −/− CD47 −/− mice reconstituted with human bone marrow, liver, and thymus) (Melkus et al, 2006).…”

Section: Current Gaps In Hiv Vaccinology Are Not Just Knowledge-bamentioning

confidence: 99%

Humanized Immunoglobulin Mice

Verkoczy

2017

Advances in Immunology

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A vaccine that can effectively prevent HIV-1 transmission remains paramount to ending the HIV pandemic, but to do so, will likely need to induce broad neutralizing antibody (bnAb) responses. A major technical hurdle towards achieving this goal has been a shortage of animal models with the ability to systematically pinpoint roadblocks to bnAb induction and to rank vaccine strategies based on their ability to stimulate bnAb development. Over the past six years, immunoglobulin (Ig) knock-in (KI) technology has been leveraged to express bnAbs in mice, an approach that has enabled elucidation of various B-cell tolerance mechanisms limiting bnAb production and evaluation of strategies to circumvent such processes. From these studies, in conjunction with the wealth of information recently obtained regarding the evolutionary pathways and paratopes/epitopes of multiple bnAbs, it has become clear that the very features of bnAbs desired for their function will be problematic to elicit by traditional vaccine paradigms, necessitating more iterative testing of new vaccine concepts. To meet this need, novel bnAb KI models have now been engineered to express either inferred pre-rearranged V(D)J exons (or unrearranged germline V, D, or J segments that can be assembled into functional rearranged V(D)J exons) encoding predecessors of mature bnAbs One encouraging approach that has materialized from studies using such newer models is sequential administration of immunogens designed to bind progressively more mature bnAb predecessors. In this review, insights into the regulation and induction of bnAbs based on the use of KI models will be discussed, as will new Ig KI approaches for higher-throughput production and/or altering expression of bnAbs in vivo, so as to further enable vaccine-guided bnAb induction studies.

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Humanized mice for HIV and AIDS research

Cited by 58 publications

References 93 publications

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

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

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

Humanized Immunoglobulin Mice

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