Abstract
A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues. These limitations are common in many humanized mouse models and are critical issues that need to be addressed. As distinct defects exist in each model, we need to be cautious about the experimental design and interpretation of the outcomes obtained using humanized mice. Considering this point, we mainly characterize the current conventional humanized mouse reconstituted only with HSCs and describe past achievements in this area, as well as the potential contributions of the humanized mouse models for the study of HIV pathogenesis and therapy. We also discuss the use of various technologies to solve the current problems. Humanized mice will contribute not only to the pre-clinical evaluation of anti-HIV regimens, but also to a deeper understanding of basic aspects of HIV biology.
Highlights
Mice reconstituted with human hematopoietic cells are called humanized mice and are applied as in vivo small animal models for the investigation of functional human immune cells and human-specific pathogens, including human immunodeficiency virus (HIV) [1,2,3,4].Their advantages include the fact that: (i) almost all tissues, including the central nervous system (CNS), which is hardly accessible in living humans, are available at different stages of HIV infection; (ii) humanized mice can be maintained at lower cost than non-human primate (NHP) models; and (iii) unlike the NHP model which requires the modification of HIV genome, HIV can efficiently replicate in the humanized mice
When we investigated cord blood (CB)-hematopoietic stem cells (HSC)-NOJ mice that were singly or simultaneously infected with R5 HIV-1 and X4 HIV-1 using isogenic virus strains harboring DsRed or EGFP (R5: NL-AD8-D or X4: NL-E, respectively), we found that the X4 HIV-1 infection of CCR5+ CD4+ T cells was suppressed in the presence of R5 HIV-1 [77]
We showed that Foxp3Low Th17-like cells are induced in the spleen when CB-HSC-NOJ mice are transfected in vivo with human FMS-like tyrosine kinase 3 ligand (FLT3L)
Summary
Mice reconstituted with human hematopoietic cells are called humanized mice and are applied as in vivo small animal models for the investigation of functional human immune cells and human-specific pathogens, including human immunodeficiency virus (HIV) [1,2,3,4]. Their advantages include the fact that: (i) almost all tissues, including the central nervous system (CNS), which is hardly accessible in living humans, are available at different stages of HIV infection; (ii) humanized mice can be maintained at lower cost than non-human primate (NHP) models; and (iii) unlike the NHP model which requires the modification of HIV genome, HIV can efficiently replicate in the humanized mice. Humanized mouse models using non-obese diabetic (NOD)/SCID/IL2Rγnull (NSG or NOG), NOD/Rag1null /IL2Rγnull (NRG), and BALB/c/Rag2null /IL2Rγnull (DKO/BRG) mice are called “current-generation models” [8].
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