%0 Journal Article %J Nature %D 2006 %T Restoring function in exhausted CD8 T cells during chronic viral infection. %A Barber, Daniel L %A Wherry, E John %A Masopust, David %A Zhu, Baogong %A Allison, James P %A Sharpe, Arlene H %A Freeman, Gordon J %A Ahmed, Rafi %K Animals %K Antigens, CD %K Antigens, CD274 %K Antigens, CD80 %K Antigens, Differentiation %K Antigens, Surface %K Apoptosis Regulatory Proteins %K CD8-Positive T-Lymphocytes %K Cell Proliferation %K Chronic Disease %K CTLA-4 Antigen %K Gene Expression Regulation %K Immune Tolerance %K Lymphocytic Choriomeningitis %K Lymphocytic choriomeningitis virus %K Membrane Glycoproteins %K Mice %K Peptides %K Programmed Cell Death 1 Receptor %K Substrate Specificity %K Virus Diseases %X Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections. %B Nature %V 439 %P 682-7 %8 2006 Feb 9 %G eng %N 7077 %1 http://www.ncbi.nlm.nih.gov/pubmed/16382236?dopt=Abstract %R 10.1038/nature04444