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Programmed Death 1 Expression on HIV-Specific CD4⁺ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction¹

Michelle D’Souza^*, Andrew P. Fontenot^*,, Doug G. Mack^*, Catherine Lozupone, Stephanie Dillon^*, Amie Meditz^*, Cara C. Wilson^*,, Elizabeth Connick^* and Brent E. Palmer^2,*

^* Department of Medicine and Department of Immunology, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262; and Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309

Functional impairment of HIV-specific CD4⁺ T cells during chronic HIV infection is closely linked to viral replication and thought to be due to T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4⁺ and CD8⁺ T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4⁺ T cells. To investigate the role of PD-1 in HIV-associated CD4⁺ T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN--producing HIV-specific CD4⁺ T cells compared with total or CMV-specific CD4⁺ T cells in untreated HIV-infected subjects (p = 0.0001 and p < 0.0001, respectively). PD-1 expression on HIV-specific CD4⁺ T cells from subjects receiving antiretroviral therapy was significantly reduced (p = 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4⁺ T cells and plasma viral load (r = 0.71; p = 0.005). PD-1 expression was significantly higher on HIV-specific T cells in the lymph node, the main site of HIV replication, compared with those in the blood (p = 0.0078). Thus, PD-1 expression on HIV-specific CD4⁺ T cells is driven by persistent HIV replication, providing a potential target for enhancing the functional capacity of HIV-specific CD4⁺ T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Colorado Center for AIDS Research and by reagents provided through the National Institutes of Health AIDS Research and Reference Reagent Program.

² Address correspondence and reprint requests to Dr. Brent E. Palmer, Department of Medicine, University of Colorado at Denver and Health Sciences Center, 4200 E 9th Ave Box B164, Denver, CO 80262. E-mail address: brent.palmer{at}uchsc.edu

³ Abbreviations used in this paper: T_Em cell, effector memory T cell; PD-1, programmed death 1; LCMV, lymphocytic choriomeningitis virus; ART, antiretroviral therapy; CEF, CMV-EBV-influenza virus; SEB, staphylococcal enterotoxin B; MFI, mean fluorescence intensity; PD-L1, PD-1 ligand 1; PD-L2, PD-1 ligand 2; FMO, fluorescence^–1; DC, dendritic cell; mDC, myeloid DC; pDC, plasmacytoid DC.

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