Abstract
Humanized mice reconstituted with human hematopoietic cells have been developed as an experimental animal model for human immunodeficiency virus type 1 (HIV-1) infection. Myeloablative irradiation is usually performed to augment the engraftment of donor hematopoietic stem cells (HSCs) in recipient mice; however, some mouse strains are susceptible to irradiation, making longitudinal analysis difficult. We previously attempted to construct humanized NOD/SCID/JAK3null (hNOJ) mice, which were not irradiated prior to human HSC transplantation. We found that, over time, many of the reconstituted CD4+ T cells expanded with an activated effector memory phenotype. Therefore, the present study used hNOJ mice that were irradiated (hNOJ (IR+)) or not (hNOJ (IR−)) prior to human HSC transplantation to examine whether the development and cellularity of the reconstituted CD4+ T cells were influenced by the degree of chimerism, and whether they affected HIV-1 infectivity. Indeed, hNOJ (IR+) mice showed a greater degree of chimerism than hNOJ (IR−) mice. However, the conversion of CD4+ T cells to an activated effector memory phenotype, with a high percentage of cells showing Ki-67 expression, occurred in both hNOJ (IR+) and hNOJ (IR−) mice, probably as a result of lymphopenia-induced homeostatic expansion. Furthermore, when hNOJ (IR+) and hNOJ (IR−) mice, which were selected as naïve- and memory CD4+ T cell subset-rich groups, respectively, were infected with CCR5-tropic HIV-1 in vivo, virus replication (as assessed by the plasma viral load) was delayed; however, the titer subsequently reached a 1-log higher level in memory-rich hNOJ (IR−) mice than in naïve-rich hNOJ (IR+) mice, indicating that virus infectivity in hNOJ mice was affected by the different status of the reconstituted CD4+ T cells. Therefore, the hNOJ mouse model should be used selectively, i.e., according to the specific experimental objectives, to gain an appropriate understanding of HIV-1 infection/pathogenesis.
Highlights
Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS) in humans, infects CD4+ T cells as well as macrophages and dendritic cells by binding to its primary receptor, CD4, and a co-receptor, usually CCR5 or CXCR4 [1,2,3]
These results indicate that irradiation augments the chimerism of human hematopoietic cells due to the enhanced engraftment of hematopoietic stem cells (HSCs) in the bone marrow (BM) of humanized NOD/SCID/JAK3null (hNOJ)
It was assumed that homeostatic peripheral expansion (HPE)-type homeostatic proliferation (HSP) might occur in hNOJ mice, as described elsewhere [27,28]; we examined the IFN-c-producing capacity of CD4+ T cells isolated from the spleens of hNOJ (IR+) and hNOJ (IR2) mice (n = 3 and n = 3, respectively) during the later phase (16 and 26 wk, respectively) post-transplantation by stimulating them with or without phorbol 12-myristate 13-acetate (PMA) plus ionomycin
Summary
Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS) in humans, infects CD4+ T cells as well as macrophages and dendritic cells by binding to its primary receptor, CD4, and a co-receptor, usually CCR5 or CXCR4 [1,2,3]. Is the tropism of HIV-1 determined by its use of either CCR5 or CXCR4, but factors such as cellular activation status, differentiation and maturation status, cell type, and the histological location of the target cells determine HIV-1 infectivity with respect to its replication, dissemination, and latency [4,5,6]. Mice reconstituted with human hematopoietic cells, referred to as humanized mice, have recently attracted attention as experimental animal models of HIV-1 infection [7,8,9,10,11,12].
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