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Clinical and Vaccine Immunology, April 2007, p. 391-396, Vol. 14, No. 4
1071-412X/07/$08.00+0     doi:10.1128/CVI.00403-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Use of a Novel Chimeric Mouse Model with a Functionally Active Human Immune System To Study Human Immunodeficiency Virus Type 1 Infection{triangledown}

Dong Sung An,1 Betty Poon,2 Raphael Ho Tsong Fang,2 Kees Weijer,3 Bianca Blom,3 Hergen Spits,3 Irvin S. Y. Chen,1,2,5,6 and Christel H. Uittenbogaart2,4,5,6*

Departments of Medicine,1 Microbiology, Immunology, and Molecular Genetics,2 Pediatrics,4 UCLA AIDS Institute,5 Jonsson Comprehensive Cancer Center, David E. Geffen School of Medicine at UCLA, Los Angeles, California,6 Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands3

Received 29 October 2006/ Returned for modification 4 January 2007/ Accepted 8 February 2007

The goal of this study was to develop a small-animal model to study human immunodeficiency virus type 1 (HIV-1) pathogenesis in blood and primary and secondary lymphoid organs. Rag2–/–{gamma}c–/– mice that are neonatally injected with human CD34+ cells develop a functional human immune system (HIS), with human hematopoietic cells being found in the thymuses, peripheral blood, spleens, and bone marrow of the animals (hereafter these animals are referred to as HIS-Rag2–/–{gamma}c–/– mice). HIS-Rag2–/–{gamma}c–/– mice were infected with small amounts of CCR5-tropic HIV-1. Viral replication and immunophenotypic changes in the human cells in peripheral blood and lymphoid organs were examined. The productive infection of human cells in peripheral blood, thymus and spleen tissue, and bone marrow was detected. Ratios of CD4+ T cells to CD8+ T cells in the infected animals declined. Although no specific anti-HIV-1 immune responses were detected, immunoglobulin M (IgM) and IgG antibodies to an unidentified fetal calf serum protein present in the virus preparation were found in the inoculated animals. Thus, we have shown that the HIS-Rag2–/–{gamma}c–/– mouse model can be used for infection with low doses of CCR5-tropic HIV-1, which is most commonly transmitted during primary infections. HIS-Rag2–/–{gamma}c–/– mice can serve as a small-animal model for investigating HIV-1 pathogenesis and testing potential HIV-1 therapies, and studies with this model may replace some long and costly studies with nonhuman primates.

* Corresponding author. Mailing address: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1747. Phone: (310) 825-1982. Fax: (310) 206-1318. E-mail: uittenbo{at}ucla.edu

{triangledown} Published ahead of print on 21 February 2007.

Clinical and Vaccine Immunology, April 2007, p. 391-396, Vol. 14, No. 4
1071-412X/07/$08.00+0     doi:10.1128/CVI.00403-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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