ABSTRACT
HIV-1 disease progression is associated with persistent immune activation. However, the nature of this association is incompletely understood. Here, we investigated immune activation in the CD4 T cell compartment of chronically HIV-1 infected individuals from Rakai, Uganda. Levels of CD4 T cell activation, assessed as co-expression of PD-1, CD38 and HLA-DR, correlated directly to viral load and inversely to CD4 count. Deeper characterization of these cells indicated an effector memory phenotype with relatively frequent expression of Ki67 despite their PD-1 expression, and levels of these cells were inversely associated with FoxP3+ regulatory T cells. We therefore use the term deregulated effector memory (DEM) cells to describe them. CD4 T cells with a DEM phenotype could be generated by antigen stimulation of recall responses in vitro. Responses against HIV-1 and CMV antigens were enriched among the DEM CD4 T cells in patients, and the diverse Vß repertoire of DEM CD4 T cells suggested they include diverse antigen-specificities. Furthermore, the levels of DEM CD4 T cells correlated directly to soluble CD14 (sCD14) and IL-6, markers of innate immune activation, in plasma. The size of the activated DEM CD4 T cell subset was predictive of the rate of disease progression, whereas IL-6 was only weakly predictive and sCD14 was not predictive. Taken together, these results are consistent with a model where systemic innate immune activation and chronic antigen stimulation of adaptive T cell responses both play important roles in driving pathological CD4 T cell immune activation in HIV-1 disease.
Subject(s)
Adaptive Immunity/immunology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , HIV Infections/virology , HIV-1/immunology , Immunity, Innate/immunology , Lymphocyte Activation/immunology , ADP-ribosyl Cyclase 1/metabolism , Adolescent , Adult , Antigens, CD/metabolism , Antigens, Viral/immunology , Apoptosis Regulatory Proteins/metabolism , CD4-Positive T-Lymphocytes/immunology , Cell Proliferation , Chronic Disease , Disease Progression , Female , HIV Infections/blood , HIV Infections/immunology , HLA-DR Antigens/metabolism , Humans , Immunologic Memory/immunology , Interleukin-6/blood , Lipopolysaccharide Receptors/blood , Male , Middle Aged , Programmed Cell Death 1 Receptor , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Uganda , Young AdultABSTRACT
NK cells are important innate immune effector cells, normally characterized as CD56(+)CD3(-) lymphocytes. In this study, we report that CD56(-)CD16(+) NK cells expand in many patients with chronic hepatitis C virus infection. These CD56(-) NK cells were functionally impaired with respect to cytokine production upon target cell recognition, in comparison to CD56(dim) and CD56(bright) NK cell subsets. In particular, CD56(-) NK cells were strikingly defective in their polyfunctional response as measured by the coexpression of MIP-1beta, IFN-gamma, TNF-alpha, and CD107a degranulation. The ability of these cells to mediate three or four of these functions was poor; expression of MIP-1beta alone dominated their response. CD56(-) NK cells retained expression of receptors such as the natural cytotoxicity receptors and NKG2D, whereas the expression of CD57 and perforin was lower when compared with CD56(dim) NK cells. Interestingly, pretreatment levels of CD56(-) NK cells correlated with the outcome of pegylated IFN-alpha and ribavirin treatment. In patients with CD56(-) NK cells in the range of healthy subjects, 80% reached a sustained virological response to treatment, whereas only 25% of patients with levels clearly above those in healthy subjects experienced a sustained virological response. Thus, chronic hepatitis C virus infection is associated with an expansion of CD56(-) NK cells functionally skewed toward MIP-1beta production only. Furthermore, high levels of these cells reveal a disturbance in innate cellular immunity that is associated with an impaired ability to respond to antiviral treatment with IFN-alpha and ribavirin.
Subject(s)
CD56 Antigen/immunology , Chemokine CCL4/immunology , Hepatitis C, Chronic/immunology , Interferon-alpha/therapeutic use , Killer Cells, Natural/immunology , Ribavirin/therapeutic use , Adult , Antiviral Agents/therapeutic use , CD56 Antigen/metabolism , CD57 Antigens/immunology , CD57 Antigens/metabolism , Cell Degranulation/drug effects , Cell Degranulation/immunology , Chemokine CCL4/metabolism , Female , Hepatitis C, Chronic/drug therapy , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Killer Cells, Natural/metabolism , Killer Cells, Natural/virology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/virology , Lysosomal-Associated Membrane Protein 1/immunology , Lysosomal-Associated Membrane Protein 1/metabolism , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily K/immunology , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Perforin/immunology , Perforin/metabolism , Receptors, Natural Killer Cell/immunology , Receptors, Natural Killer Cell/metabolism , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.
