This Date In UCSF History: Studying HIV On Transplanted Human Tissue

Originally published in Synapse - The UCSF student newspaper on Dec. 3, 1990

How can one study the effects of human immunodeficiency virus (HIV) on living human tissues without infecting people with HIV? A not-so-obvious answer is to transplant human tissues into mice and then infect the mice with HIV.

This approach was the brainstorm of J. Michael McCune, an immunologist who studies HIV as scientific director of Systemix, a research corporation in Palo Alto, and also treats AIDS patients at San Francisco General Hospital.

McCune graduated from Harvard in 1976 and received his PhD. and M.D. degrees from Rockefeller-Cornell 1981 and 1982, respectively. He did his residency in medicine at UCSF from 1982 through 1984, and has been working at SF General since then. He became scientific director at Systemix in 1988.

He came up with the transplant idea three years ago while working as a postdoctoral fellow in the department of pathology at Stanford University Medical School.

“Unfortunately we know very little about the way in which [the HIV virus] causes disease,” he told Synapse. “

A relevant animal model would be useful because then we could infect the animal with the virus and step by step come to understand how HIV destroys the immune system.

“The cells that the virus infects are human,” McCune explains, “and those cells usually reside in human organs. So to make a relevant animal model we had to devise a means by which to insert human 'organs' into a mouse.”

The technique that McCune's group at Systemix has developed essentially replaces the normal immune system of a mouse with a functional human immune system.

To do this, special mutant mice that lack immune systems of their own are surgically implanted with rice-sized pieces of human fetal organs —specifically, liver, thymus and lymph nodes.

These particular organs were chosen for their critical roles in the formation and development of the immune system.

Once inside the mouse, the human transplants arc supplied with blood from nearby vessels and they eventually grow and develop into functional organ segments, working in parallel with the analagous mouse organs which arc still present.

Although the transplants are foreign, the mouse cannot reject them because it lacks its own immune system. It was McCune's insight that the transplanted human immune system would not reject the mouse body because they arc fetal cells, still too immature to recognize the mouse as foreign.

Once the transplanted organs have had time to produce a competent immune system, the mice can then be infected with HIV or a number of other human viruses to study the virus’ effects on the human organs and the human immune system's response to the viral infection.

Opportunistic solutions

Another major focus of McCune's research is to study the effects of various drugs such as AZT (azidothymidine) and ddl (didcoxyinosine) on HIV infection.

He will also begin work soon on combination drug therapies aimed at fighting AlDS associated opportunistic infections such as PCP (Pneumocystis carinii pneumonia) and toxoplasmosis in conjunction with HIV infection.

“Later we will need to have therapies that we can use against HIV [itself].” observes McCune, “but in all patients who arc infected with HIV, we have to give other drugs against other bugs, so we have to have systems where we can study combinations of drugs against combinations of infectious agents, and we plan to do that first with HIV plus toxoplasmosis.”

McCune feels that the drug studies will probably be the first area of his research to become clinically relevant.

“With AZT for instance, in a three-to-four week experiment, we were able to determine the [optimum] dose range of AZT that is very similar to the dose range that we use now in man. In humans, in clinical trials, it took about four to five years to come up with that number.”

He is now trying to determine optimum dosages for other drugs, including ddl.

McCune is also conducting studies with his mice to determine whether AZT treatment soon after exposure to HIV is indeed helpful, and if so, at what dosages.

Studies such as this, which for obvious reasons cannot be done in humans, may provide information useful for the future treatment of health-care workers who arc exposed to HIV in the workplace.

The two aspects of McCune's career complement each other neatly, allowing for more rapid and fruitful advances both on the benchtop and in the clinic.

Describing how his research at Systemix may influence the treatment of AIDS patients, McCune commented, “The intent of the company is to use technology to develop new treatments for human disease states.

“The technique we have developed [human organ implants in mice] is one that enables us to more quickly look at therapies for HIV and perhaps other viruses. It also allows us to potentially isolate human hematopoietic stem cells and to make monoclonal antibodies —all of these arc things which could be brought into the clinic later as new therapies.”

McCune's clinical work also benefits his research, he says.

“We're using [HIV] isolates from patients in the animals so as to have the system be even more relevant than if we were using, for instance, HIV isolates that were grown in tissue culture.”

And it was his work with AIDS patients at SF General that first convinced him to make the epidemic his research focus.