Last year, J. Victor Garcia's group at the University of Texas described a technique that allows immunodeficient mice to be reconstituted with a human immune system. Although there are still issues in terms of potential confounding crosstalk between mouse and human immune system components in this and similar "humanized mouse" models, they may offer a useful tool for studying approaches to the treatment and prevention of HIV. Today, J.Victor Garcia's group reports another step in this direction in the online first section of the Journal of Experimental Medicine. The researchers successfully infected humanized mice intrarectally with HIV, leading to CD4 depletion broadly resembling that seen in humans. Notably, the study used the laboratory HIV strain LAI for this experiment and since this is an X4 virus it will be important to find out if similar results can be obtained with R5-using HIV strains. Also, while the study claims that the phenotype of gut CD4 T cells in this system is similar to humans and macaques, there are significant differences in terms of CXCR4 expression (most human gut CD4 T cells co-express CXCR4 and CCR5, whereas CXCR4 expression on gut T cells in the humanized mice was low).
The Journal of Experimental Medicine
Published online 26 March 2007
doi:10.1084/jem.20062411
BRIEF DEFINITIVE REPORT
Zhifeng Sun1, Paul W. Denton1, Jacob D. Estes2, Florence A. Othieno1, Bangdong L. Wei1, Anja K. Wege1, Michael W. Melkus1, Angela Padgett-Thomas1, Mary Zupancic2, Ashley T. Haase2, and J. Victor Garcia1
1 Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390
2 Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455
Intrarectal infection between men who have sex with men represents a predominant form of human immunodeficiency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate that human lymphocytes generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract of humanized mice with human CD4+ T cells rendering them susceptible to intrarectal HIV transmission. HIV infection after a single intrarectal inoculation results in systemic infection with depletion of CD4+ T cells in gut-associated lymphoid tissue and other pathologic sequela that closely mimics those observed in HIV infected humans. This novel model provides the basis for the development and evaluation of novel approaches aimed at immune reconstitution of human gut-associated lymphoid tissue and for the development, testing, and implementation of microbicides to prevent intrarectal HIV-1 transmission.
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