Stanford Scientists Manage to Infect ‘Human’ Mice With AIDS
Stanford scientists have made a major advance in AIDS research by transmitting the disease to mice that have a human immune system.
The infected mice, experts said, promise to be valuable tools for studying the development of AIDS as well as for testing new drugs and vaccines. The production of mice with human immune systems was announced only three months ago, after the Stanford scientists had implanted fetal human immune tissues into a special strain of immune-deficient mice.
Stanford immunologist Irving L. Weissman and his colleagues report in today’s Science journal that they successfully infected the mice with the human immunodeficiency virus (HIV), which causes AIDS, and have been able to observe early stages in the development of the disease.
Researchers have long been frustrated in their attempts to achieve true AIDS in chimpanzees and other animals. The development of such animal models is a crucial step in research into the causes, treatments and possible vaccines for any disease.
The new model seems particularly valuable because it is human cells that are infected, even though they are in mice, and results obtained with them should be directly translatable into human therapies.
Scientists from the National Institutes of Health report in the same issue of Science new details on a mouse model of AIDS they created by inserting the HIV deoxyribonucleic acid (DNA) into mouse embryos, producing animals that have the viral genes in all of their cells. This animal model, though quite different from the Stanford model, can also be used for testing drugs and studying the progression of the disease.
“These (two reports) are fundamental basic science breakthroughs that will have very important implications in understanding the pathogenesis of infection, the molecular virology of HIV, treatment approaches, and vaccine development,” said immunologist Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. “All areas will benefit from the models.”
“They are both very major advances,” said immunologist David Scott of the University of Rochester Cancer Center. “Both are very exciting.”
Researchers have been unable to infect mice with HIV in the past because the surface of mouse cells does not contain a key protein, called a receptor, that allows the virus to enter the cells. Chimpanzees, which are expensive in addition to being an endangered species, can be infected by HIV, but do not develop AIDS symptoms.
Researchers have thus had difficulty studying proliferation of the virus and testing drugs and vaccines. “We desperately need . . . a good small-animal model, such as these mice,” said Martin Hirsch, a professor of medicine at Harvard.
The Stanford mice were created by implanting human fetal liver, thymus and lymph node tissues from abortion clinics into a strain of mice that lack an immune system and therefore cannot reject the human tissues. Weissman and his colleagues had previously reported that these tissues grow and form an intact human immune system that protects the mice from infectious disease.
Visiting immunologist Reiko Namikawa and post-doctoral fellow Joseph M. McCune injected HIV into the mice’s implanted thymus and lymph nodes. Within two weeks, cells throughout the immune system were infected and the virus spread to other cells over the following six weeks. “It’s indisputable that we have an infection that spread,” Weissman said in a telephone interview.
Because all the mice were sacrificed within eight weeks after HIV injection, the Stanford team did not observe AIDS symptoms in the animals. They are now monitoring a second group of mice for the expected development of such symptoms, Weissman said.
Another team of scientists, led by immunologist Donald E. Mosier of the Medical Biology Institute, a small research foundation in La Jolla, also announced in September that they had created a human immune system in mice by injecting human white blood cells into immune-deficient mice. Mosier said in a telephone interview Thursday that his group had also successfully infected the animals with HIV, but had not yet published the results.
In the National Institutes work, the first generation of 12 mice created by molecular biologist Malcolm A. Martin and his colleagues showed no sign of disease, although they had HIV genes in their cells. But when these animals were mated with normal mice, one of them produced eight litters of mice that developed an AIDS-like condition immediately after birth and died within 25 days. The researchers are not sure why the offspring of the other 11 did not develop the symptoms despite having had the HIV genes in their cells.
The National Institutes model would be good for testing drugs designed to prevent the virus from expressing itself after infection. It also shows how the virus affects cells throughout the body, an important development, Fauci said.
The Weissman model and his own are more “biologically relevant,” Mosier said, because the infected cells are human rather than mouse. The National Institutes model does not involve the actual transfer of the virus from cell to cell, as it occurs in humans, giving it limited value in studying new drugs and vaccines that would halt or prevent such transfer.
But “it is missing the point to say one is more relevant than the other,” Fauci said. “They are both extremely important, with each having its own advantages and disadvantages. We’ll learn a lot from each.”
Unfortunately, researchers will not learn much from the National Institutes mice for a while because 127 of the 130 transgenic mice were lost in an accident earlier this month. To prevent escape of the HIV virus, the mice are kept in a special airtight facility. When the air conditioning in the facility was shut down for repairs, the mice died of heat prostration. Six months will be required to build up the colony again.
