New Humanized Mouse Model May Accelerate HIV Vaccine Development

Researchers report on a new mouse model with an improved humanized immune system that far more accurately reflects the human response to HIV infection.

Development of an effective HIV vaccine requires a greater understanding of how human immune responses succeed or fail to control HIV. The new study, reported in the July 18, 2012, issue of the journal Science Translational Medicine, was designed to test a modification of a humanized mouse model created by transplanting human bone marrow stem cells, along with other human tissue, into otherwise immunodeficient BLT mice. Assistant Prof. Andrew Tager, MD, director of the Massachusetts General Hospital (Boston, MA, USA) Humanized Mouse Program, said that in earlier work, "multiple researchers have contributed to dramatic improvements in the ability of humanized mice to model human diseases [and] have demonstrated that this particular humanized mouse model reproduces many aspects of the human immune response." Lead author Timothy Dudek, PhD, of the Ragon Institute, adds, "But there has been little evidence regarding whether they reproduce the interaction between HIV and the human immune system."

The research team, based at the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard (Ragon Institute; Charlestown, MA, USA) created groups of humanized BLT mice using cells and tissues from human donors with different alleles of HLA molecules, which flag infected cells for destruction by CD8 T-cells. Particular HLA alleles, such as HLA-B57, are more common in individuals naturally able to control HIV, and some of the mice generated in this study expressed this important protective allele. Six weeks after the mice had been infected with HIV-1, the virus rapidly evolved in critical regions known to be targeted by CD8(+) T-cells. This observation indicated not only that these mice mounted human-like cellular immune responses against HIV-1, but also that the virus was mutating to avoid those responses in a manner similar to that seen in humans. Mice expressing the protective HLA-B57 exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans.

Use of the traditional rhesus monkey - Simian immunodeficiency virus (SIV) in vivo model is very limited scientifically, ethically, and economically. Senior author Todd Allen, PhD and associate professor of medicine, said "We are currently studying whether we can induce human HIV-specific immune responses in these [mice] by vaccination, which would provide a rapid, cost-effective model to test the ability of different vaccine approaches to control or even block HIV infection. If we can do this, we'll have a very powerful new tool to accelerate HIV vaccine development, one that also may be useful against other pathogens."

Related Links:
Ragon Institute of MGH, MIT, and Harvard
Massachusetts General Hospital