Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection.

Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1-specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRß sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution.

BLT humanized mice as a small animal model of HIV infection.

Humanized mice are valuable models for the research and development of vaccine strategies and therapeutic interventions to control or eradicate HIV. The BLT humanized mouse model is particularly promising because the combination of transplantation of human fetal pluripotent hematopoietic stem cells with surgical engraftment of human fetal thymic tissue results in improved T cell reconstitution, maturation, and selection. To date, the BLT humanized mouse model has been used to study many aspects of HIV infection including prevention, mucosal transmission, HIV-specific innate and adaptive immunity, viral latency, and novel antiretroviral and immune-based therapies for suppression and reservoir eradication. Here we describe recent advances and applications of the BLT humanized mouse model of HIV infection and discuss opportunities to further improve this valuable small animal model.