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.

Abstract

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.

• Authors: Satoru Watanabe, Kazuo Terashima, Shinrai Ohta, Shigeo Horibata, Misako Yajima, Yoko Shiozawa, M Zahidunnabi Dewan, Zhong Yu, Mamoru Ito, Tomohiro Morio, Norio Shimizu, Mitsuo Honda, Naoki Yamamoto
• Journal: Blood (Blood) Vol. 109 Issue 1 Pg. 212-8 (Jan 01 2007) ISSN: 0006-4971 [Print] United States
• PMID: 16954502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR5 protein, human
• DNA, Viral
• HIV Antibodies
• Interleukin Receptor Common gamma Subunit
• Receptors, CXCR4
• Receptors, CXCR5
• Receptors, Chemokine

Topics

• Animals
• Bone Marrow (pathology, virology)
• CD4-Positive T-Lymphocytes (virology)
• Cell Lineage
• Cord Blood Stem Cell Transplantation
• DNA, Viral (analysis)
• Disease Models, Animal
• Disease Susceptibility
• Female
• HIV Antibodies (biosynthesis, blood)
• HIV Infections (immunology)
• Humans
• Interleukin Receptor Common gamma Subunit (deficiency, genetics)
• Lymphocyte Subsets (pathology)
• Lymphoid Tissue (pathology, virology)
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Receptors, CXCR4 (analysis, genetics)
• Receptors, CXCR5
• Receptors, Chemokine (analysis, genetics)
• Spleen (pathology, virology)
• Thymus Gland (pathology, virology)
• Transplantation, Heterologous
• Viremia (immunology)