Identification of PD-1 as a Unique Marker for Failing Immune Reconstitution in HIV-1–Infected Patients on Treatment

Katharina Grabmeier-Pfistershammer, MD; Peter Steinberger, PhD; Armin Rieger, MD; Judith Leitner, MSc; Norbert Kohrgruber, MD

Disclosures

J Acquir Immune Defic Syndr. 2011;56(2):118-124. 

In This Article

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.[1–3] 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.[4,5] 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.[5,6] 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.[6–8] Furthermore, certain components of cART like zidovudine, tenofovir, and didanosine have been associated with impaired immune reconstitution.[9,10]

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.[11] Chronic immune activation in HIV-infected patients leads to exhaustion and premature senescence of the immune system.[12] 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.[13] Importantly, expression of PD-1 is highly correlated with impaired T-cell function and functional senescence of the immune system.[14] High level of PD-1 expression is a general phenomenon in chronic viral infection and has been shown in mice and men.[14,15] Blocking of PD-1/PD-L pathways restores T-cell function in vitro.[16,17] 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.[15,18] 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.[19]

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).

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