Contrary to the widely held belief that the thymus -- an organ essential for producing competent immune cells -- is not functional in adulthood, researchers at the Gladstone Institute of Virology and Immunology have shown that half of the HIV-infected patients in a recent study appear to have substantial thymus function.
Thymus function in HIV-infected patients may mean that their bodies can compensate for the loss of T cells caused by HIV by re-awakening a dormant thymus and producing healthy T cells to fight off HIV infection. It also raises the possibility of therapies to replenish the immune system, by thymus stimulation or transplant, for those without a working thymus.
"Given the evidence that HIV can infect and destroy the thymus, this is an outcome that is not predicted by textbooks or clinical experience," said Joseph M. McCune, MD, PhD, associate professor of medicine at UC San Francisco, and an associate investigator at the UCSF-affiliated Gladstone Institute of Virology and Immunology, located at San Francisco General Hospital. McCune, who is the lead investigator of the study, said, "It is surprising not only that abundant thymic tissue could be found in these patients, but also that the percentage showing such tissue was so high."
"For patients over 40, it's a clear black and white difference, since in every uninfected individual over 40 that we looked at, we never saw thymus," he said. "Yet among those over 40 infected with HIV, five out of the ten had abundant thymus tissue."
Among the 99 HIV-positive patients in that study, the size of the thymus corresponded to the number of T cells circulating in the patient's blood, regardless of age: a larger thymus meant more T cells. All but one of the patients under 40 who were in the early stages of HIV disease progression had abundant thymic tissue, indicating that the thymus might be triggered into action by the first losses of T cells.
The research findings are reported in the June 1 issue of the Journal of Clinical Investigation, with an accompanying commentary by Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Disease, and his co-workers.
The thymus is an organ located at the base of the neck and is the source of the "T" in T cell. In newborns and young children, it acts as a teacher of T cells, sending out "naive" T cells -- those which have not seen foreign invaders. Once a naive cell encounters a foreign particle, it becomes dedicated to reacting to that particular particle. As that cell multiplies, it passes on its information as a memory T cell. By late puberty, education of the T cells is complete, and the thymus is considered to be non-functional.
In uninfected people, memory T cells circulate for many years, but with HIV-infection, the virus kills these cells. About three years ago, with the increasing use of anti-retroviral therapies, AIDS patients began to show increases in their numbers of T cells. "We began to wonder where the T cells of HIV infected people on anti-retroviral therapy were coming from," said McCune. "Were the lone T cell survivors multiplying or were new ones being produced? It was time to ask the question: 'Can the thymus work in HIV-infected adults?'"
To study the thymus noninvasively, McCune and his colleagues used a procedure called computed tomography to create images of the thymus. They sent the films to two radiologists at the University of Michigan Ann Arbor for size ratings. To correlate the size of the thymus with its function, the UCSF researchers used an antibody test that recognizes two markers on the surface of naive T cells.
"The finding of thymus function in half of the patients raises the possibility that there are different mechanisms of HIV infection and different ways that AIDS progresses," said McCune. "For those who have abundant thymus, it is possible that new T cells may be readily made. For those who do not, these studies may lead to insights about how to turn the thymus 'on' again."
The director of the Gladstone Institute of Immunology and Virology, Warner Greene, MD, PhD, added, "These are exciting and unexpected results that have potential implications for immune restoration following the control of HIV infection."
The study was funded by the National Institutes of Health and the University of California San Francisco. In large part, it was made possible by the assistance of Project Inform and ACT UP Golden Gate, two local AIDS activist groups that encouraged the work and helped to recruit subjects into the study.
Co-investigators from the Gladstone Institute of Virology and Immunology are Diane Schmidt, BS, senior research associate, and Robert Grant, MD, MPH, MS, Staff Research Scientist and Director of the UCSF/Gladstone Core Virology Lab. Collaborators formerly of the Gladstone Institute of Virology and Immunology are Rick Loftus and Lisa Swor-Yim (both currently medical students at UCSF) Pamela Carroll, and Devon Webster. Collaborators from the University of Michigan Ann Arbor are Isaac Francis, MD, and Barry Gross, MD, both professors of radiology.
All AIDS research at UCSF is coordinated by the UCSF AIDS Research Institute. Directed by Thomas Coates, PhD, who also is a UCSF professor of medicine, epidemiology and biostatistics, the UCSF ARI is an institute without walls that encompasses all UCSF AIDS programs under a single umbrella. The ARI includes a dozen research institutes, a wide range of clinical, behavioral science, and policy programs, and nearly 1,000 investigators.