Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection

TY - JOUR

T1 - Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection

AU - Jost, Stephanie

AU - Moreno-Nieves, Uriel Y

AU - Garcia-Beltran, Wilfredo F

AU - Rands, Keith

AU - Reardon, Jeff

AU - Toth, Ildiko

AU - Piechocka-Trocha, Alicja

AU - Altfeld, Marcus

AU - Addo, Marylyn Martina

PY - 2013/1/1

Y1 - 2013/1/1

N2 - BACKGROUND: Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.RESULTS: We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.CONCLUSIONS: Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

AB - BACKGROUND: Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.RESULTS: We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.CONCLUSIONS: Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.

KW - Anti-Retroviral Agents

KW - Antiretroviral Therapy, Highly Active

KW - Dendritic Cells

KW - Galectins

KW - Gene Expression Regulation

KW - HIV Infections

KW - HIV-1

KW - Host-Pathogen Interactions

KW - Humans

KW - Killer Cells, Natural

KW - Membrane Proteins

KW - Monocytes

U2 - 10.1186/1742-4690-10-74

DO - 10.1186/1742-4690-10-74

M3 - SCORING: Journal article

C2 - 23866914

VL - 10

SP - 74

JO - RETROVIROLOGY

JF - RETROVIROLOGY

SN - 1742-4690

ER -