Of Mice and Men: Using “Humanized” Mice to Fight HIV
By Jeffrey Laurence, M.D.
November 10, 2008— A major impediment to the design of new interventions against HIV/AIDS such as protective vaccines and microbicides is the lack of a good model with which to test these interventions outside of the test tube. Small non-human primates such as rhesus monkeys are very expensive to acquire and study. They also cannot be infected with HIV itself; scientists must use a monkey virus relative known as SIV, and it is not always easy to know whether an approach that is effective against SIV would also work for HIV.
The lab mouse would be an ideal subject but it has been difficult for scientists to generate and agree on a good mouse model, the immune system of which is both susceptible to HIV infection and subsequently responds to HIV infection in ways similar to what is observed in humans. But in April 2007, amfAR-funded scientists led by Dr. Liguo Zhang of the University of North Carolina at Chapel Hill published a paper in the journal Blood describing a model using genetically immune deficient mice that were “humanized” by injecting human stem cells.
The following year, in the October 2008 issue of Blood, Dr. Zhang and former amfAR grantee Dr. Derya Unutmaz reported on experiments using these mice to explore an important issue in the immune control of HIV infection. They focused on a special type of immune CD4+ T cell known as Treg (pronounced tee-reg) or “regulatory T cell.” What these cells attempt to regulate, in diseases from hepatitis to cancer in autoimmune disorders, are counterproductively overactive immune response, which could cause injury if left unchecked. It has been known for some time that Tregs are especially susceptible to HIV infection. And it was believed that the persistent immune activation characteristic of chronic HIV infection, whether or not the person is receiving HIV therapy, might be a consequence of the depletion of these cells early on in HIV infection. But evidence of this was lacking.
Dr. Zhang and colleagues first showed that Tregs were present in the blood and all immune organs of their model mice. They then injected these animals with HIV obtained from a person who had rapidly progressed from initial infection to AIDS, and demonstrated that the Treg cells were indeed preferentially infected and destroyed by the virus. However, if they first gave the mice a special toxin, denileukin difitox, designed specifically to deplete Treg cells, the number of infected cells was markedly diminished, as well as the amount of free virus in the blood after a subsequent HIV exposure.
This suggested two things to Dr. Zhang and colleagues. First, Tregs are key targets for initial HIV infection and growth, during a period when most other T cells are resting and not susceptible to HIV replication. Second, by impairing the function of Tregs, HIV may contribute to the immune activation that is characteristic of HIV disease and that has been implicated in many AIDS-related conditions including heart disease, diabetes, and osteoporosis. These investigators now plan to use their Treg toxin to study potential treatments in chronically infected mice.
Dr. Laurence is amfAR’s senior scientific consultant.