Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors

Exhaustion of virus-specific T cells may play an important role in the pathophysiology of chronic viral infections. Here, we analyzed telomere length and telomerase activity in HIV-1-specific CD8(+) T cells from progressors or controllers to determine underlying molecular pathways of T-cell exhaustion and senescence. Telomere lengths of HIV-1-specific CD8(+) T cells from progressors were significantly shorter compared with autologous cytomegalovirus (CMV)/Epstein-Barr virus (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 stabilization in controllers corresponded to high levels of constitutive telomerase activity, which was associated with preservation of cytotoxic and proliferative properties. Conversely, limited constitutive telomerase 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. Collectively, these data suggest a causal role of telomere shortening for the functional deficiencies of HIV-1-specific CD8(+) T cells in chronic progressive infection, while high constitutive telomerase activities appears to contribute to maintenance of polyfunctional HIV-1-specific CD8(+) T cells from HIV-1 controllers. (Blood. 2008; 112: 3679-3687)