The Humanized Mouse Model: What Added Value Does It Offer for HIV Research?

Abstract

In the early 2000s, novel humanized mouse models based on the transplantation of human hematopoietic stem and progenitor cells (HSPCs) into immunocompromised mice were introduced (hu mice). The human HSPCs gave rise to a lymphoid system of human origin. The HIV research community has greatly benefitted from these hu mice. Since human immunodeficiency virus (HIV) type 1 infection results in a high-titer disseminated HIV infection, hu mice have been of great value for all types of HIV research from pathogenesis to novel therapies. Since the first description of this new generation of hu mice, great efforts have been expended to improve humanization by creating other immunodeficient mouse models or supplementing mice with human transgenes to improve human engraftment. Many labs have their own customized hu mouse models, making comparisons quite difficult. Here, we discuss the different hu mouse models in the context of specific research questions in order to define which characteristics should be considered when determining which hu mouse model is appropriate for the question posed. We strongly believe that researchers must first define their research question and then determine whether a hu mouse model exists, allowing the research question to be studied.

Humanized mice for studying HIV latency and potentially its eradication

“…In this work, they transplanted human CD34 + cord blood cells into newborn immunocompromised mice, resulting in the development of human, B, T and dendritic cells, structured primary and secondary lymphoid organs and functional immune responses. Subsequently, various immune-deficient mouse strains have been created and evaluated for human immune engraftment, offering valuable platforms for biomedical research [5].…”

“…LTIs are essential for the organogenesis of secondary lymphoid tissue [54], which is crucial for adaptive immune responses [55]. The absence of LTI in humanized mice results in poorly developed lymphoid organs and weak or no adaptive immune responses [5]. This is particularly noteworthy in HIV studies, as HIV targets CD4 + T cells, which play a vital role in coordinating adaptive immune responses [56].…”

“…For instance, human IL-15 improve the function of human NK cells [58], and more recently, human thymic-stromal-cell derived lymphopoietin for LTI cells for better generation of secondary lymphoid tissue [59]. In our recent discussion of the existing models in the context of HIV research [5], we concluded that the research question should determine the particular type of mouse strain. There is no standout humanized mouse model for its superior and robust adaptive immune response.…”

“…In summary, the ‘humanized mouse field’ has made tremendous progress over the past two decades, resulting in various humanized mice that need to be carefully selected based on the specific research question [5].…”

“…Please note HIV is a human-specific pathogen and does not infect conventional small laboratory animals. Humanized mouse models include: hu-PBMCs/PBLs employing peripheral blood mononuclear cells (PBMCs) or human peripheral blood lymphocytes (BPLs) from human donors; hu-HSCs generated by injection of purified human CD34+ hematopoietic stem cells (HSC); and hu-BTL (bone marrow, thymus, liver) models generated by the implantation of human fetal liver and thymus tissues together with injection of HSCs [5,6] (see Box 1 for the nomenclature of humanized mice). We will highlight the importance of ongoing research efforts and exploration of various tools, including studies on latent reservoirs, to progress towards the goal of an HIV cure.…”