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

Abstract

Galectin-9 (Gal-9) is a b-galactosidase-binding lectin that promotes apoptosis, tissue inflammation, and T cell immune exhaustion, and alters HIV infection in part through engagement with the T cell immunoglobulin mucin domain-3 (Tim-3) receptor and protein disulfide isomerases (PDI). Gal-9 was initially thought to be an eosinophil attractant, but is now known to mediate multiple complex signaling events that affect T cells in both an immunosuppressive and inflammatory manner. To understand the kinetics of circulating Gal-9 levels during HIV infection we measured Gal-9 in plasma during HIV acquisition, in subjects with chronic HIV infection with differing virus control, and in uninfected individuals. During acute HIV infection, circulating Gal-9 was detected as early as 5 days after quantifiable HIV RNA and tracked plasma levels of interleukin (IL)-10, tumor necrosis factor (TNF)-a, and IL-1b. In chronic HIV infection, Gal-9 levels positively correlated with plasma HIV RNA levels (r = 0.29; p = 0.023), and remained significantly elevated during suppressive antiretroviral therapy (median: 225.3 pg/ml) and in elite controllers (263.3 pg/ml) compared to age-matched HIV-uninfected controls (54 pg/ml). Our findings identify Gal-9 as a novel component of the first wave of the cytokine storm in acute HIV infection that is sustained at elevated levels in virally suppressed subjects and suggest that Gal-9:Tim-3 crosstalk remains active in elite controllers and antiretroviral (ARV)-suppressed subjects, potentially contributing to ongoing inflammation and persistent T cell dysfunction.

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 + T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

“…We studied individuals from three cohorts of prospectively observed HIV-infected subjects: the Toronto-based cohort (Maple Leaf Clinic and St. Michael's Hospital, Toronto, Canada), the San Francisco-based SCOPE (Study of the Consequences of the Protease Inhibitor Era, San Francisco, U.S.) cohort, and the San Francisco-based Blood Systems cohort. Samples were obtained from subjects comprising the following patient groups: (1) treatment-naive acute HIV infection (infected Ͻ6 months, with detectable viral load, HIV Western blot serology negative); (2) treatment-naive early HIV infection (infected Ͻ6 months, with detectable viral load, HIV Western blot serology positive); (3) treatment-naive chronic HIV infection (infected Ͼ1 year, with detectable viral load); (4) HAART-treated chronic HIV infection (treated for Ͼ6 months, undetectable viral load); (5) treatment-naive chronic HIV infection with elite viral control (elite controllers; untreated, HIV infected with undetectable viral load, as previously described [34]); (6) demographically matched HIV-seronegative subjects. The Toronto-based cohort consisted of samples from groups 2 (n ϭ 15), 3 (n ϭ 22), 4 (n ϭ 5), and 6 (n ϭ 13).…”

“…The Toronto-based cohort consisted of samples from groups 2 (n ϭ 15), 3 (n ϭ 22), 4 (n ϭ 5), and 6 (n ϭ 13). The SCOPE cohort consisted of samples from groups 3 (n ϭ 16), 4 (n ϭ 19), 5 (n ϭ 18), and 6 (n ϭ 16), as previously described (34). The Blood Systems cohort consisted of plasma samples from groups 1 (n ϭ 19) and 2 (n ϭ 13) as previously described (35).…”

“…While it is unclear which ligand interaction signals through Tim-3 on T cells to induce negative signaling, sTim-3 has the potential to "mop up" these soluble proteins, or block phosphatidylserine or CEACAM1 interactions, reducing their bioavailability to Tim-3 as well as other receptors. Indeed, this may prove beneficial, as levels of plasma galectin-9 are significantly elevated in HIV infection and correlate with disease progression (34).…”

Engineering galectin–glycan interactions for immunotherapy and immunomodulation

“…75 In addition to viral entry, galectin-9 systemically overexpressed during acute and chronic stages of HIV infection likely contributes to persistent inflammation and systemic T-cell dysfunction. 76 Owing to the importance of galectins as extracellular signals in pathological T-cell dysfunction, there is increasing interest in therapeutics that can inhibit galectin-T-cell interactions. One approach is to eliminate galectin-1 or its cognate glycans.…”

Modulation of TIM-3 expression on NK and T cell subsets in HIV immunological non-responders

“…Galectin-9 is a β-galactoside binding lectin that is increased in the plasma of patients with acute HIV infection and HAART has been reported to reduce plasma galectin-9 levels in HIV patients [8][9][10]. Galectin-9 has been described to suppress T h 1 responses by binding to T cell immunoglobulin-and mucindomain-containing molecule-3 (TIM-3) on terminally differentiated T h 1 cells [11,12].…”