IMMUNOBIOLOGY

play an important role in the pathophysi-ology of chronic viral infections. Here, we analyzed telomere length and telomerase activity in HIV-1–specific CD8 T cells from progressors or controllers to deter-mine underlying molecular pathways of T-cell exhaustion and senescence. Telo-mere lengths of HIV-1–specific CD8 T cells from progressors were signifi-cantly shorter compared with autologous cytomegalovirus (CMV)/Epstein-Barr vi-rus (EBV)–specific CD8 T cells or bulk CD8 T cells, while telomere lengths from controllers significantly exceeded those of autologous bulk CD8 T cells and reached a similar level as HIV-1–specific CD8 T cells collected during primary HIV-1 infection. Telomere length stabiliza-tion in controllers corresponded to high levels of constitutive telomerase activity, which was associated with preservation of cytotoxic and proliferative properties. Conversely, limited constitutive telomer-ase activity was observed in HIV-1– specific CD8 T cells from progressors, although an increase in both telomere length and telomerase activity was achieved in antigenic-peptide–stimulated cells from progressors after blocking the PD-1/PD ligand 1 (PD-L1) pathway. Collec-tively, these data suggest a causal role of telomere shortening for the functional deficiencies of HIV-1–specific CD8T cells in chronic progressive infection, while high constitutive telomerase activities ap-pears to contribute to maintenance of polyfunctional HIV-1–specific CD8 T cells from HIV-1 controllers. (Blood. 2008;112