Galectin-9 is rapidly released during acute HIV-1 infection and remains sustained at high levels despite viral suppression even in elite controllers.
Galectin-9 (Gal-9) is a β-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)-α, and IL-1β. 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.
1 Hawaii Center for AIDS, Department of Tropical Medicine, University of Hawaii , John A. Burns School of Medicine, Honolulu, Hawaii.
Ravi
R
Tandon
Glen M
GM
Chew
Mary M
MM
Byron
Persephone
P
Borrow
Toshiro
T
Niki
Mitsuomi
M
Hirashima
Jason D
JD
Barbour
Philip J
PJ
Norris
Marion C
MC
Lanteri
Jeffrey N
JN
Martin
Steven G
SG
Deeks
Lishomwa C
LC
Ndhlovu
D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D037161:Galectins / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D044966:Anti-Retroviral Agents; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508609:IL10 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019704:Protein Disulfide-Isomerases