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

Abstract

BackgroundNatural 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.ResultsWe 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.ConclusionsOur 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.

Accumulation of Cytotoxic CD16+NK Cells in Simian Immunodeficiency Virus-Infected Lymph Nodes Associated withIn SituDifferentiation and Functional Anergy

“…Although Tim-3 expression can actually delineate mature cytotoxic NK cells, its engagement results in suppression of cytotoxicity (33). Indeed, the ligand for Tim-3, Gal-9, is increased in HIV patients, and the continued exposure of Tim-3 ϩ NK cells to ligands leads to exhaustion and/or anergy (34), which could explain our observations. Recent reports specific to SIV-infected macaques indicate that Tim-3 also delineates exhausted T cells in SIV infection and that they accumulate in lymph nodes during disease (35).…”

TIM-family proteins inhibit HIV-1 release

“…However, it is currently unknown if TIM-1 plays a role in HIV-1 replication and infection, although reduced TIM-3 expression on NK cells has been reported to be associated with chronic HIV-1 infection (18). Here we report that TIM-1 inhibits HIV-1 release, resulting in decreased virus production.…”

Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

“…79 The elevated Gal-9 level in ARV-suppressed subjects may be attributed to the presence of unspliced cellular HIV RNA. Soluble Gal-9 levels have been shown to be elevated in the plasma of HIV-infected subjects, [65][66][67] and Jost et al 66 have shown that despite ARV therapy, chronic HIV-infected adults did not experience declines in plasma Gal-9 levels when compared to untreated chronic HIV-infected subjects. Elite controllers maintaining a viral load of < 50 copies/ml represent less than 1% of all untreated HIV-infected patients.…”

“…33,60,62,63 During chronic HIV infection, Gal-9-expressing Treg cells are presumed to selectively suppress the proliferation of nonprotective HIVspecific CD8 + T cells with high Tim-3 levels, but not protective HIV-specific CD8 + T cells with low levels of Tim-3. 64 Soluble Gal-9 levels have been shown to be elevated in the plasma of HIV-infected subjects, [64][65][66] suggesting that Gal-9 may play an important role in HIV pathogenesis. Engagement of Gal-9 with Tim-3 + CD4 + T cells in vitro renders CD4…”