What happens to lymphocytes that are specific for persistent infections? Most adult humans are chronically infected with several viruses, including Epstein-Barr virus and cytomegalovirus. Chronic HIV and Hepatitis C virus infections are large public health concerns. Here, investigators analyzed T cells in mice infected with one of two strains of a virus: one strain is quickly cleared while a nearly identical strain becomes a chronic infection. They found that a protein, programmed cell death 1 or PD-1, was increased on the surface of CD8+ “killer” T lymphocytes in chronically infected mice. PD-1 is previously identified as an inhibitory molecule on T cells that binds PD-L1, which is expressed on most cells in the body. (PD-1 also binds PD-L2, expressed on dendritic cells and macrophages.) PD-1 expression normally increases transiently after infection but remains elevated on specific T cells in chronically infected mice. Could persistent infections be cleared through PD-1 blockade? The final result presented here sounds a cautionary note: these viruses kill mice genetically deficient in PD-1 (knockouts), apparently due to an excessive immune response.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R.. "Restoring function in exhausted CD8 T cells during chronic viral infection." Nature. 2006 Feb 9;439:682-7.
Saturday, January 27, 2007
T cell changes in chronic infection
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Co-infection?
The authors state that there are only 3 amino acid differences between the strain of lymphocytic choriomeningitis virus (LCMV) that causes acute infections (Armstrong) and the strain that causes chronic infection (strain 13). They also say that none of the changes involve T cell epitopes and, to their credit, they analyze many T cell specificities. This is especially interesting in light of recent findings showing that virulence of the 1918 flu was not due to the immunodominant hemagglutinin (H) or neuraminidase (N) proteins (BMN story).
These authors could test the epitope similarity or identity by co-infecting -- strain 13 might protect Armstrong from clearance. Dominance of chronic infection would be predicted from their model of increased PD-1.
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