Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses.
Critical to the development of an effective HIV/AIDS model is the production of an animal model that reproduces long-lasting active replication of HIV-1 followed by elicitation of virus-specific immune responses. In this study, we constructed humanized nonobese diabetic/severe combined immunodeficiency (NOD/SCID)/interleukin-2 receptor gamma-chain knockout (IL2Rgamma(null)) (hNOG) mice by transplanting human cord blood-derived hematopoietic stem cells that eventually developed into human B cells, T cells, and other monocytes/macrophages and 4 dendritic cells associated with the generation of lymphoid follicle-like structures in lymphoid tissues. Expressions of CXCR4 and CCR5 antigens were recognized on CD4+ cells in peripheral blood, the spleen, and bone marrow, while CCR5 was not detected on thymic CD4+ T cells. The hNOG mice showed marked, long-lasting viremia after infection with both CCR5- and CXCR4-tropic HIV-1 isolates for more than the 40 days examined, with R5 virus-infected animals showing high levels of HIV-DNA copies in the spleen and bone marrow, and X4 virus-infected animals showing high levels of HIV-DNA copies in the thymus and spleen. Furthermore, we detected both anti-HIV-1 Env gp120- and Gag p24-specific antibodies in animals showing a high rate of viral infection. Thus, the hNOG mice mirror human systemic HIV infection by developing specific antibodies, suggesting that they may have potential as an HIV/AIDS animal model for the study of HIV pathogenesis and immune responses.
Watanabe
Satoru
S
Department of Virology, Division of Medical Science, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Terashima
Kazuo
K
Ohta
Shinrai
S
Horibata
Shigeo
S
Yajima
Misako
M
Shiozawa
Yoko
Y
Dewan
M Zahidunnabi
MZ
Yu
Zhong
Z
Ito
Mamoru
M
Morio
Tomohiro
T
Shimizu
Norio
N
Honda
Mitsuo
M
Yamamoto
Naoki
N
D000818:Animals; D001853:Bone Marrow / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D019070:Cell Lineage; D036101:Cord Blood Stem Cell Transplantation; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D015483:HIV Antibodies / Q000096:biosynthesis* / Q000097:blood; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D016131:Lymphocyte Subsets / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology* / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D019718:Receptors, CXCR4 / Q000032:analysis / Q000235:genetics; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine / Q000032:analysis / Q000235:genetics; D013154:Spleen / Q000473:pathology / Q000821:virology; D013950:Thymus Gland / Q000473:pathology / Q000821:virology; D014183:Transplantation, Heterologous; D014766:Viremia / Q000276:immunology*
C095085:CXCR5 protein, human; D004279:DNA, Viral; D015483:HIV Antibodies; D053631:Interleukin Receptor Common gamma Subunit; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine