"HIV infection ultimately depletes the body of CD4 T cells, making it impossible to mount an immune response," said Timothy W. Schacker, M.D., associate professor of medicine and author of the study. "For the first time, we show that one mechanism of this depletion is damage to the structure that these cells need to maintain a normal-sized population and to mount an immune response to other infections. In essence, the T cell home is destroyed."
Researchers enrolled 11 individuals at various stages of HIV/AIDS infection. Their goal was to understand the specific changes that happen in the population of cells most directly affected by HIV--the CD4 T cells. These cells are responsible for coordinating the immune response and are the primary target for HIV infection and replication. Researchers biopsied and examined the lymph node tissue before and during treatment for HIV. They have developed sensitive methods to precisely measure both the size of the CD4 population in lymphatic tissue and the amount of scar tissue accumulated in the T cell zone.
Researchers noted two significant findings. First, the size of the CD4 T cell population measured in peripheral blood (commonly done to stage the disease and determine the effects of treatment) does not accurately reflect the size of the population in lymph tissues. "You could have a reasonable peripheral count and a very poor count in lymph tissues," said Schacker.
Second, the amount of fibrosis and scar tissue in the T cell zone was significantly related to the size of the CD4 population in that space (i.e. the more scar tissue, the fewer cells) and the recovery of the CD4 population with therapy. The researchers suggest the process of destruction is analogous to what is seen in chronic active hepatitis.
"We knew that T cells are destroyed by direct viral replication," said Schacker, "but we now know that the population is unable to recover to a normal size because the environmental niche used to support the cells is destroyed. New CD4 T cells are unable to get into the space they need to be in to function, and there is no space for the cells to divide."
One implication of this discovery is that through testing of the lymph nodes (similar to what is done to stage cancer), physicians might accurately stage the disease and predict the response to standard therapies.
"This is essentially a new concept in how HIV infection causes damage to the human immune system," said Schacker. "Our observation may explain why up to 25 percent of people placed on HIV therapy may have good viral suppression but still have no significant increase in T cell count.
"Currently, most treatment strategies for HIV/AIDS focus on stopping the virus from replicating itself in the body, which is essential to begin the process of immune reconstitution, but it does not happen for everyone. These findings suggest that therapies targeting the damage from inflammation and accumulation of scar tissue might enhance current antiviral therapy."
The work was performed at the university's General Clinical Research Center, part of the Academic Health Center. The work was supported by the National Institutes of Health.
The Academic Health Center is home to the University of Minnesota's seven health professional schools and colleges as well as several health-related centers and institute. Founded in 1851, the University is one of the oldest and largest land grant institutions in the country. The AHC mission is to prepare the new health professionals who improve the health of communities, discover and deliver new treatments and cures and strengthen the economy.
Additional Contacts:
Timothy Schacker, M.D., University of Minnesota Medical School
Sarah Youngerman, Academic Health Center, 612-624-4604
Journal
Journal of Clinical Investigation