Humanized NSG Mouse Models of HIV-1 Infection and Pathogenesis

Latinovic os
2016 Journal of Human Virology & Retrovirology  
Another alternative approach has been to implant human stem cells (HSC) into newborn NSG mice. Both models provide a suitable environment in which to partially reconstitute the human immune system. With adequate numbers of target cells, HIV-1 can replicate without interference from the mouse immune system. The NSG mouse transplantation/engraftment models are the best currently available, as they provide the highest level of human HSC engraftment compared with other immunodeficient strains
more » ... Discussion Small animal models that successfully and closely mimic the human immune system are acutely needed in biomedical research. In this regard, the NOD.Cg-Prkdc scid IL2rg tm1Wjl mouse strain (NSG) is better suited for in vivo research purposes than other SCID/NOG strains [3] because; they harbor a scid mutation and an interleukin 2 (IL-2) receptor common gamma chaintargeted mutation (IL2rg null ). As a result, these NSG mice lack mature T-, B -cells and functional natural killer (NK) cells. These mice are not only deficient in the above listed lineages, but also in cytokine signaling, and they permit the development of the above listed lineages of human origin, as well as in the development of human macrophages [1]. The Il2rg null mutation overcame some previous limitations including minimal donor chimerism and poor expansion of lymphoid cells [4, 5] . The model supports the development of a functional human immune system, allowing detailed analyses of human immune physiology and function [5] . Furthermore, the genotype does not lead to development of thymomas, which occur in 30% of classic NSG mice by the age of 6 months. Clearly this model is a good option for short term experiments of up to 4 weeks following HIV-1 infection [5, 6] . The model was used to engraft human PBMCs into adult mice to study the effects of HIV-1 entry blockage by INK128, a prototype TOR-KI (the catalytic inhibitor, in dual targeting of mTORC-1/2) [7] . It was also reported that in comparison with all immunodeficient strains, the NSG mouse model has highest human HSC engraftment levels [8] . All together, it makes this xenotransplantion model as the "gold standard" for in vivo studies. Our previous studies demonstrated that after intraperitoneal (i.p.) injection with PBMCs, NSG adult mice were able to support robust HIV-1 replication, developing high serum p24 levels and progressively lower CD4+T cell levels, as measure by flow cytometry. Specifically, we showed that when the mice were injected i.p. with 20,000 of 50% tissue culture infective dose (TCID 50% ) of HIV-1 Bal, they developed a productive infection [6] . Quantifying CD4+ T cells, CCR5+ cells, and CCR5 expression levels to evaluate and validate the NSG adult mouse model, we showed that levels of both CD4+ and CCR5+ cells from within the CD4+ T cell population remained stable in non-infected mice up to 4 weeks post engraftment [6] . As expected, infected mice showed a steep decline in CD4+ T cells and CCR5+ cells, as well as somewhat reduced CCR5 expression levels [6] . A second approach, based upon the injection of HSC into newborn mice supports longer-term experiments and allows multilineage development of human immune cells. Mice transplanted with fetal liver and thymus tissues are useful to replicate HIV-1 induced pathology and to test hematopoietic stem cell-based gene therapy. That and the utilization of the human adaptive immune system in cord blood cell-transplanted mice led to the development of a mouse model in which CD34+ cells were transplanted into the liver of newborn mice. This results in the development of a lymphoid-like system of human origin with Tand B-cells, monocytes, plasmacytoid and conventional dendritic
doi:10.15406/jhvrv.2016.03.00088 fatcat:rfg6vssq35edtfc2iniwg3a2ua