High Levels of Human Peripheral Blood Mononuclear Cell Engraftment and Enhanced Susceptibility to Human Immunodeficiency Virus Type 1 Infection in NOD/LtSz-scid/scid Mice

Abstract

Inbred C.B-17-scid/scid mice accept human peripheral blood mononuclear cell (PBMC) xenografts and are susceptible to human immunodeficiency virus type 1 (HIV-1) infection, but low levels of PBMC engraftment impede use of this system in HIV research. This report describes the effect of host strain background on human PBMC engraftment and HIV infectivity in scid mice. Back-crossing the scid mutation to the NOD/Lt strain (designated NOD/LtSz-scid/scid) increased the percentage of engrafted human PBMC in recipient spleens by 5- to 10-fold compared with that in C.B-17-scid/scid stock. Four weeks after human PBMC-injected mice were infected with HIV-1, 79% of NOD/LtSz-scid/scid spleens harbored replicating virus compared with only 39% of spleens in C.B-17-scid/scid mice. The NOD/LtSz-scid/scid mouse may provide a useful small animal model for studies of HIV-1.

NOD/LtSz-Rag1nullMice: An Immunodeficient and Radioresistant Model for Engraftment of Human Hematolymphoid Cells, HIV Infection, and Adoptive Transfer of NOD Mouse Diabetogenic T Cells

“…Three, 4, and 8 wk after HIV-1 infection, mice were killed and blood and spleen samples were collected. The samples were analyzed for percentages of human CD45 ϩ cells by flow cytometry and for the presence of HIV-1 DNA and RNA by PCR, as previously described (1,36). Spleen cell samples for flow cytometry were analyzed with the panel of human mAb used for the PBMC-engrafted mice described above.…”

“…It is unknown which specific innate immune defect, or combination of defects lead to enhanced engraftment with high levels of human hematolymphoid cells. Markedly decreased levels of human lymphoid cell engraftment are associated with increased levels of innate immunity in other strains of scid mice (1,12). Based on our published data, NODLtSz-scid mice are now the strain of choice for most laboratories studying engraftment of human hematolymphoid cells in immunodeficient mice (1, 8 -10, 13-18).…”

“…T he establishment of a functional human immune system reconstituting a small animal model is a goal of many workers investigating human immunity and human-specific infectious agents such as HIV-1 (1)(2)(3). Since the first reports of low levels of engraftment of human hematolymphoid cells in C.B-17 mice homozygous for the severe combined immunodeficiency (Prkdc scid ) mutation (hereafter abbreviated as scid) (3)(4)(5), we have focused on optimizing this model by manipulating the host strain background to increase levels of human cell engraftment.…”

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

“…Nonobese diabetic (NOD)/SCID mice exhibit reduced NK activity, macrophage function and serum hemolytic complement activity in addition to the deficit in mature T and B cells [24,25]. Although increased huT cell engraftment levels and X-GVHD have been reported for NOD/SCID mice, these mice are still constrained by the presence of residual NK cell activity and poor human CD4 + T cell engraftment [23,24,[26][27][28][29][30]. Recently, this residual NK cell activity was virtually eliminated by backcrossing the β 2 -microglobulinnull (β2m null ) allele onto the NOD/SCID background [31].…”

Human allograft rejection in humanized mice: a historical perspective

“…For example, immunodeficiency mutations on the nonobese diabetic (NOD) mouse background support higher engraftment levels of human hematopoietic cells and immune cells as compared to other backgrounds, such as BALB/c, C3H and C57BL/6. [30][31][32][33][34][35] The NOD mouse background offers a number of genetic advantages that promote the engraftment of human immune systems. 34 A direct comparison of immunodeficient IL2rc null mice on either a NOD background (NOD-scid IL2rc null (NSG) and NOD-Rag1 null IL2rc null (NRG)) or BALB/c (BALB-Rag2 null IL2rc null ) background revealed that the NOD background supported significantly higher levels of human cell engraftment following injection of human HSC.…”