PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Abstract

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

“…Several groups have recently reported that PD-1 expression on peripheral blood CD8 þ T cells is increased during HIV infection and regulate T-cell survival. [34][35][36] Herein, we also demonstrated that induction of PD-1 is increased in Mes LNs of non-controllers and expression of PD-1 is enhanced in vitro by TGF-b. Although, we speculate a role of PD-1 in Mes LNs favoring immunosupression, a formal proof that blockade of PD-1/PD-L1 interaction will restore T-cell function and prevent death remains to be addressed once adequate reagents are available.…”

“…In HIV-infected individuals, it has been shown that blocking such interaction increases the capacity of peripheral blood HIV-specific CD8 þ T cells to proliferate and survive. [34][35][36] While TGF-b appears necessary to prime cells of SIV-infected macaques to undergo apoptosis, it is not sufficient in and by itself to fully induce the process, as we have been unable to induce death by simply adding TGF-b on T cells from healthy macaques, in spite of inducing PD-1 expression. This may however reflect the lack of PD-L1 expression in our in vitro culture system.…”

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

“…6,39,40 We made a similar observation when incubating total splenocytes isolated from wild-type (WT), but not PD-L1 knockout (KO) mice with anti-PD-L1 antibody (Figure 3a; compare lanes 1–2 and 3–4 in Figure 3b), thus demonstrating antibody specificity. However, co-culture of WT splenocytes with WT adipocytes significantly dampened the anti-PD-L1 antibody effect on CD8 + IFNγ + T cells (compare lanes 1–2 and 5–6 in Figure 3b).…”

How Ebola and Marburg viruses battle the immune system

“…These trends have been confirmed in human studies showing that elevated levels of B7-H1 (REF. 47) and PD1 (REFS 48,49) are associated with T-cell exhaustion and depletion in HIV, and T-cell function can be restored in vitro by using B7-H1-specific antibody to antagonize the co-inhibitory interaction between B7-H1 and PD1. The commonality between these and other earlier observations of the importance of co-inhibition mediated by B7-H1-PD1 interactions is that they involve chronic conditions.…”