Abstract and Introduction
Abstract
PD-1 expression on T cells correlates with T-cell exhaustion and disease progression in HIV-infected patients. Previous studies have shown that combinational antiretroviral therapy induced viral suppression results in immune restoration and reduced PD-1 expression. However, a significant number of patients fail to restore CD4 T cells despite suppression of HIV replication below limit of quantification. In this study, we have analyzed PD-1 expression on CD4 and CD8 T cells in patients with poor immune reconstitution despite successful highly active antiretroviral therapy. We found that T cells of such patients express significantly higher levels of PD-1 than patients who had normal recovery of CD4 cells after treatment. In contrast, failing immune reconstitution was not associated with the expression of activation markers, indicating that PD-1 is a unique marker for failing immune reconstitution despite viral suppression. Furthermore, we show that T cells from patients with poor immune recovery differ from T cells of elderly in respect of their marker profile. PD-1 expression negatively correlated with individual CD4 cell counts, and PD-1 expressing T cells were more prone to programmed death ligand-mediated inhibition of T-cell proliferation, indicating that PD-1-mediated T-cell suppression may have a role in impaired immune reconstitution in HIV patients.
Introduction
A hallmark of HIV infection is the depletion of CD4 T cells, leading to progressive immunodeficiency, opportunistic infections, and death. Combinational antiretroviral therapy (cART) stops this process, and long-term viral suppression leads to sustained recovery of CD4 cell counts with a rapid increase within the first 3-6 months and a second slower increase lasting over several years. However, there is considerable individual variation in this process. In 10%-30% of patients, CD4 cell counts remain critically low despite treatment-induced viral suppression. Several risk factors for insufficient CD4 T cell have been defined. These include older age, treatment interruptions, incomplete viral suppression, low CD4 T-cell count before initiation of antiretroviral therapy, and coinfections like viral hepatitis. Furthermore, certain components of cART like zidovudine, tenofovir, and didanosine have been associated with impaired immune reconstitution.
Recently, it has become more and more evident that not only direct cytopathic effects of HIV but also the immune activation by chronic HIV infection leads to a profound impairment of the immune functions. Chronic immune activation in HIV-infected patients leads to exhaustion and premature senescence of the immune system. One parameter of this exhaustion is the activation-associated T-cell molecule programmed death-1 (PD-1), which by interaction with its 2 ligands, PD-L1 and PD-L2, conveys negative signals to T cells. Importantly, expression of PD-1 is highly correlated with impaired T-cell function and functional senescence of the immune system. High level of PD-1 expression is a general phenomenon in chronic viral infection and has been shown in mice and men. Blocking of PD-1/PD-L pathways restores T-cell function in vitro. In HIV-infected patients, PD-1 expression is directly correlated with individual viral loads, and effective cART has been shown to downregulate the expression of this receptor on CD4 and CD8 T cells. HIV-infected patients who can control viral replication (controller) and patients who do not progress due to very low viral loads (long-term nonprogressors) exhibit significant lower PD-1 expression as compared with patients with high levels of viral replication and progressive disease.
Previous studies have focused on PD-1 expression in viremic patients, but no detailed analysis of PD-1 expression in successfully treated aviremic patients has been done up to date. In this study, we have analyzed PD-1 expression in patients with failing immunological recovery but successful control of viral replication on sustained antiretroviral treatment (nonimmune reconstituters, non-IR).