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How do the rules of immunity change during chronic infections?

April 10, 2007

New study finds an altered immune response to viruses like HIV and hepatitis C

(PHILADELPHIA) — After a viral infection, a small percentage of the T cells generated to kill virus-infected cells remain on guard to establish long-term immunity. These so-called memory T cells, which derive from a family of immune cells known as CD8 T cells, engage in a self-renewal process that is essential to their persistence. This ongoing process ensures effective protection against any repeat infection by the same virus, even decades later.

But not all infections are equal. While most viral infections are cleared from the body within a few days or weeks, some infections, such as HIV or hepatitis C infections, become chronic. Some studies have suggested that the virus-specific CD8 T cells generated during a chronic infection may not develop the same characteristics as the CD8 T cells that persist after an acute infection.

Now, scientists at The Wistar Institute have found that the CD8 T cells generated to fight a chronic infection operate under an entirely different maintenance scheme than do the CD8 T cells that become memory T cells following an acute infection, becoming wholly dependent upon the presence of virus for their continuation. Details of the study will appear in the April 16 issue of The Journal of Experimental Medicine, published online April 9.

In addition, the CD8 T cells maintained during chronic infections establish a distinct pattern of cell division that creates a rapid turnover of cells, a characteristic that could be manipulated to design new therapeutic options for chronic infections, says E. John Wherry, Ph.D., senior author on the study and an assistant professor in the Immunology Program at Wistar.

"It appears the immune system responds to viral infections with two very different cell types," Wherry says. "In one case, when virus is completely cleared, you have a memory T cell capable of self-renewal. But during chronic infection, you have a totally different type of T cell that is not governed by the same pathways and mechanisms."

Understanding how the body's immune response operates during chronic infections, and why it fails to clear these infections, could help scientists design more effective therapies to fight chronic infections and certain types of tumors, says Wherry.

In previous studies, Wherry had shown that chronically stimulated CD8 T cells were unable to undergo the slow, steady self-renewal process used by the CD8 T cells that persist as memory T cells after an acute infection. In addition, his studies showed that CD8 T cells associated with chronic infections responded poorly to IL-7 and IL-15, growth factors needed to maintain memory T cells after an acute infection. He theorized that prolonged exposure to the virus might prevent the development of normal memory T cells.

To test his theory, Wherry and his group infected mice with a virus that simulates a chronic infection. The scientists then treated the mice to clear the virus from their systems. When the virus was cleared, the CD8 T cells that had partial function also disappeared. By not going through the normal process of self-renewal, the disappearing T cells left the mice with no long-term immunity.

"The findings suggest that we're caught in an immunological catch-22 with chronic infections," Wherry says. "The persistence of the virus is inactivating the T cells, yet the T cells are now dependent on the persisting virus for their maintenance."

The study also showed that over a four-week period, the CD8 T cells generated to fight the virus had divided five to six times, yet the number of these T cells remained relatively stable. Wherry says this observation suggests that either a very small subset of the cells are recruited to divide or that the virus-driven division of this T cell population is accompanied by extensive cell death.

Though these questions remain to be answered, the findings have implications for developing treatments for patients with chronic infections, Wherry says. "The results suggest that the rate of proliferation or cell death could perhaps be modulated to alter the size or quality of virus-specific CD8 T cell populations during persisting infections."

The Wistar Institute