Programmed death (PD)-1 molecule and its ligand PD-L1 distribution among memory CD4 and CD8 T cell subsets in human...

Human immunodeficiency virus (HIV)-1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti-HIV-1-specific responses: programmed death (PD)-1 molecule and its ligand PD-L1 are negative regulators of T cell activity and their expression is increased during HIV-1 infection. This study examines correlations between T cell maturation, expression of PD-1 and PD-L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV-1(+) and 17 uninfected individuals were phenotyped for PD-1 and PD-L1 expression on CD4(+) and CD8(+) T cell subsets. The effect of PD-1 and PD-L1 blockade on proliferation and interferon (IFN)-gamma production was tested on eight HIV-1(+) patients. Naive (CCR7(+)CD45RA(+)) CD8(+) T cells were reduced in HIV-1 aviraemic (P = 0.0065) and viraemic patients (P = 0.0130); CD8 T effector memory subsets [CCR7(-)CD45RA(-)(T(EM))] were increased in HIV-1(+) aviraemic (P = 0.0122) and viraemic (P = 0.0023) individuals versus controls. PD-1 expression was increased in CD4 naive (P = 0.0496), central memory [CCR7(+)CD45RA(-) (T(CM)); P = 0.0116], T(EM) (P = 0.0037) and CD8 naive T cells (P = 0.0133) of aviraemic HIV-1(+) versus controls. PD-L1 was increased in CD4 T(EMRA) (CCR7(-)CD45RA(+), P = 0.0119), CD8 T(EM) (P = 0.0494) and CD8 T(EMRA) (P = 0.0282) of aviraemic HIV-1(+)versus controls. PD-1 blockade increased HIV-1-specific proliferative responses in one of eight patients, whereas PD-L1 blockade restored responses in four of eight patients, but did not increase IFN-gamma-production. Alteration of T cell subsets, accompanied by increased PD-1 and PD-L1 expression in HIV-1 infection contributes to anergy and impaired anti-HIV-1-specific responses which are not rescued when PD-1 is blocked, in contrast to when PD-L1 is blocked, due possibly to an ability to bind to receptors other than PD-1.