For 30 years, the animal model of choice for HIV research has been a rhesus macaque infected with simian immunodeficiency virus (SIV). But differences between HIV and SIV, along with disparities between human and monkey immune systems, limit the effectiveness of that animal model.
“We now have an animal model that accurately replicates the human immune response to HIV,” said Todd Allen of the Ragon Institute, the senior author of the study. “And there’s the added advantage that it’s a small animal model and a lot less expensive than a primate.”
Six years ago, scientists at the University of Texas Southwestern Medical Center developed a “humanized” mouse model—a mouse carrying functional human genes, cells, or tissues—of the immune system by transplanting human bone marrow, liver, and thymus tissues into mice lacking a functional immune system. The resulting mouse, called a BLT mouse, reconstituted a human-like immune system (2).
To analyze how BLT mice might react to HIV infection, Todd Allen and colleagues at the Ragon Institute created 20 of the mice using tissues of eight human donors, each of whom had a different allele of human leukocyte antigen (HLA), a molecule that orchestrates the immune system and identifies which regions of a virus to attack.
Normal mice are not susceptible to HIV infection, but BLT mice are. The team infected the 20 mice and analyzed them during acute infection—the first 6 to 10 weeks after exposure to the virus. They tracked the CD8+ T cells response as well as where and when the virus mutated.
In both regards, infection of the BLT mice looked very similar to human HIV infection. First, the CD8+ T cell response was dependent on which HLA allele a mouse had, just as a human’s response to HIV depends on their HLA allele. The protective HLA-B*57 allele, found in humans who naturally control HIV, for example, was also protective in mice. “An animal model needs to accurately replicate that specificity,” said Allen.
In addition, the virus mutated within the first few weeks of infection—a hallmark of human HIV infection—and it mutated at the region targeted by the mouse’s specific HLA allele, just as it does in humans.
Allen’s team is now attempting to induce human HIV-specific immune responses in the BLT mice via vaccination. If the mice respond to vaccination in the same way as humans do, the new model could provide a fast, cheap way to test different HIV vaccines prior to primate trials. “There’s a lot of enthusiasm around the potential of this model,” said Allen.
1. Dudek, T.E., et al. 2012. Rapid Evolution of HIV-1 to Functional CD8+ T Cell Responses in Humanized BLT Mice. Sci Trans Med 143:143ra98.
1. Melkus, M.W., et al. 2006. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12:1316-22.