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.
Get full access to this article
View all access options for this article.
References
1.
UNAIDS: How to get to zero: Faster, smarter, better. World AIDS day report, 2011. www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/JC2216_WorldAIDSday_report_2011_en.pdf. Accessed February1, 2012.
2.
PalellaFJJr, DelaneyKM, MoormanAC, et al.: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med, 1998; 338(13):853–860.
3.
RobertsonKR, SmurzynskiM, ParsonsTD, et al.: The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS, 2007; 21(14):1915–1921.
4.
BiniEJ, ParkJ, and FrancoisF: Use of flexible sigmoidoscopy to screen for colorectal cancer in HIV-infected patients 50 years of age and older. Arch Intern Med, 2006; 166(15):1626–1631.
5.
DeeksSG and PhillipsAN: HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ, 2009; 338:a3172.
6.
AncesBM, VaidaF, YehMJ, et al.: HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis, 2010; 201(3):336–340.
7.
CurrierJS, LundgrenJD, CarrA, et al.: Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation, 2008; 118(2):e29–35.
8.
TriantVA, LeeH, HadiganC, and GrinspoonSK: Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab, 2007; 92(7):2506–2512.
9.
KirkGD, Merlo CP O D, et al.: HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Infect Dis, 2007; 45(1):103–110.
10.
OkuliczJF and LambotteO: Epidemiology and clinical characteristics of elite controllers. Curr Opin HIV AIDS, 2011; 6(3):163–168.
11.
KrishnanS, WilsonEM, SheikhV, et al.: Evidence for innate immune system activation in HIV Type 1-infected elite controllers. J Infect Dis, 2014; 209(6):931–939.
12.
AppayV and SauceD: Immune activation and inflammation in HIV-1 infection: Causes and consequences. J Pathol, 2008; 214(2):231–241.
ButlerSL, ValdezH, WestbyM, et al.: Disease-modifying therapeutic concepts for HIV in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr, 2011; 58(3):297–303.
15.
NeuhausJ, JacobsDRJr, BakerJV, et al.: Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis, 2010; 201(12):1788–1795.
16.
BurdoTH, LentzMR, AutissierP, et al.: Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. J Infect Dis, 2011; 204(1):154–163.
17.
FrenchMA, KingMS, TschampaJM, et al.: Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells. J Infect Dis, 2009; 200(8):1212–1215.
18.
BrenchleyJM, PriceDA, SchackerTW, et al.: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med, 2006; 12(12):1365–1371.
19.
SandlerNG, WandH, RoqueA, et al.: Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis, 2011; 203(6):780–790.
20.
HuntPW, CaoHL, MuzooraC, et al.: Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS, 2011; 25(17):2123–2131.
21.
LevyY, LacabaratzC, WeissL, et al.: Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest, 2009; 119(4):997–1007.
22.
SeretiI, DunhamRM, SpritzlerJ, et al.: IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood, 2009; 113(25):6304–6314.
23.
BehlerCM, VittinghoffE, LinF, et al.: Hematologic toxicity associated with interferon-based hepatitis C therapy in HIV type 1-coinfected subjects. Clin Infect Dis, 2007; 44(10):1375–1383.
24.
LugliE, MuellerYM, LewisMG, et al.: IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques. Blood, 2011; 118(9):2520–2529.
25.
GringeriA, MusiccoM, HermansP, et al.: Active anti-interferon-alpha immunization: A European-Israeli, randomized, double-blind, placebo-controlled clinical trial in 242 HIV-1-infected patients (the EURIS study). J Acquir Immune Defic Syndr Hum Retrovirol, 1999; 20(4):358–370.
26.
CrawfordTQ, NdhlovuLC, TanA, et al.: HIV-1 infection abrogates CD8+ T cell mitogen-activated protein kinase signaling responses. J Virol, 2011; 85(23):12343–12350.
27.
CapiniCJ, RichardsonMW, HendelH, et al.: Autoantibodies to TNFalpha in HIV-1 infection: Prospects for anti-cytokine vaccine therapy. Biomed Pharmacother, 2001; 55(1):23–31.
28.
CepedaEJ, WilliamsFM, IshimoriML, et al.: The use of anti-tumour necrosis factor therapy in HIV-positive individuals with rheumatic disease. Ann Rheum Dis, 2008; 67(5):710–712.
29.
WestlakeSL, ColebatchAN, BairdJ, et al.: The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: A systematic literature review. Rheumatology, 2010; 49(2):295–307.
30.
TakamuraS, Tsuji-KawaharaS, YagitaH, et al.: Premature terminal exhaustion of Friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors. J Immunol, 2010; 184(9):4696–4707.
31.
HaflerDA and KuchrooV: TIMs: Central regulators of immune responses. J Exp Med, 2008; 205(12):2699–2701.
32.
JinHT, AndersonAC, TanWG, et al.: Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA, 2010; 107(33):14733–14738.
33.
JonesRB, NdhlovuLC, BarbourJD, et al.: Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med, 2008; 205(12):2763–2779.
34.
ValiB, JonesRB, SakhdariA, et al.: HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol, 2010; 40(9):2493–2505.
35.
BlackburnSD, ShinH, HainingWN, et al.: Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol, 2009; 10(1):29–37.
36.
WherryEJ, HaSJ, KaechSM, et al.: Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity, 2007; 27(4):670–684.
37.
BengschB, SeigelB, RuhlM, et al.: Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog, 2010; 6(6):e1000947.
38.
NakanjakoD, SsewanyanaI, Mayanja-KizzaH, et al.: High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort. BMC Infect Dis, 2011; 11:43.
39.
SauceD, LarsenM, FastenackelsS, et al.: HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood, 2011; 117(19):5142–5151.
40.
WadaJ and KanwarYS: Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J Biol Chem, 1997; 272(9):6078–6086.
41.
AndersonAC, AndersonDE, BregoliL, et al.: Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science, 2007; 318(5853):1141–1143.
42.
DaiSY, NakagawaR, ItohA, et al.: Galectin-9 induces maturation of human monocyte-derived dendritic cells. J Immunol, 2005; 175(5):2974–2981.
43.
NagaharaK, ArikawaT, OomizuS, et al.: Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions. J Immunol, 2008; 181(11):7660–7669.
44.
JayaramanP, Sada-OvalleI, BeladiS, et al.: Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med, 2010; 207(11):2343–2354.
45.
ZhuC, AndersonAC, SchubartA, et al.: The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol, 2005; 6(12):1245–1252.
46.
ArikawaT, SaitaN, OomizuS, et al.: Galectin-9 expands immunosuppressive macrophages to ameliorate T-cell-mediated lung inflammation. Eur J Immunol, 2010; 40(2):548–558.
47.
OomizuS, ArikawaT, NikiT, et al.: Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner. Clin Immunol, 2012; 143(1):51–58.
48.
SekiM, OomizuS, SakataKM, et al.: Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol, 2008; 127(1):78–88.
49.
IrieA, YamauchiA, KontaniK, et al.: Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer. Clin Cancer Res, 2005; 11(8):2962–2968.
50.
ImaizumiT, KumagaiM, SasakiN, et al.: Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol, 2002; 72(3):486–491.
51.
MengsholJA, Golden-MasonL, ArikawaT, et al.: A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One, 2010; 5(3):e9504.
52.
WienerZ, KohalmiB, PoczaP, et al.: TIM-3 is expressed in melanoma cells and is upregulated in TGF-beta stimulated mast cells. J Invest Dermatol, 2007; 127(4):906–914.
53.
WangF, WanL, ZhangC, et al.: Tim-3-galectin-9 pathway involves the suppression induced by CD4+CD25+ regulatory T cells. Immunobiology, 2009; 214(5):342–349.
54.
HastingsWD, AndersonDE, KassamN, et al.: TIM-3 is expressed on activated human CD4(+) T cells and regulates Th1 and Th17 cytokines. Eur J Immunol, 2009; 39(9):2492–2501.
55.
QiuY, ChenJ, LiaoH, et al.: Tim-3-expressing CD4(+) and CD8(+) T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. PLoS Pathog, 2012; 8(11):e1002984.
56.
OomizuS, ArikawaT, NikiT, et al.: Cell surface galectin-9 expressing th cells regulate th17 and foxp3(+) treg development by galectin-9 secretion. PloS One, 2012; 7(11):e48574.
57.
NikiT, TsutsuiS, HiroseS, et al.: Galectin-9 is a high affinity IgE-binding lectin with anti-allergic effect by blocking IgE-antigen complex formation. J Biol Chem, 2009; 284(47):32344–32352.
58.
BiS, HongPW, LeeB, and BaumLG: Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci USA, 2011; 108(26):10650–10655.
59.
SharmaS, SundararajanA, SuryawanshiA, et al.: T cell immunoglobulin and mucin protein-3 (Tim-3)/galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci USA, 2011; 108(47):19001–19006.
60.
SehrawatS, ReddyPB, RajasagiN, et al.: Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog, 2010; 6(5):e1000882.
61.
RangachariM, ZhuC, SakuishiK, et al.: Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med, 2012; 18(9):1394–1400.
62.
ClaytonKL, HaalandMS, Douglas-VailMB, et al.: T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J Immunol, 2014; 19(2):782–791.
63.
TandonR, GiretMT, SenguptaD, et al.: Age-related expansion of Tim-3 expressing T cells in vertically HIV-1 infected children. PloS One, 2012; 7(9):e45733.
64.
ElahiS, DingesWL, LejarceguiN, et al.: Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat Med, 2011; 17(8):989–995.
65.
Chagan-YasutanH, SaitohH, AshinoY, et al.: Persistent elevation of plasma osteopontin levels in HIV patients despite highly active antiretroviral therapy. Tohoku J Exp Med, 2009; 218(4):285–292.
66.
JostS, Moreno-NievesUY, Garcia-BeltranWF, et al.: Dysregulated Tim-3 expression on natural killer cells is associated with increased galectin-9 levels in HIV-1 infection. Retrovirology, 2013; 10:74.
67.
ElahiS, NikiT, HirashimaM, and HortonH: Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection. Blood, 2012; 119(18):4192–4204.
68.
StaceyAR, NorrisPJ, QinL, et al.: Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol, 2009; 83(8):3719–3733.
69.
LeitnerJ, RiegerA, PicklWF, et al.: TIM-3 does not act as a receptor for galectin-9. PLoS Pathog, 2013; 9(3):e1003253.
70.
JonesRB, NdhlovuLC, BarbourJD, et al.: Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med, 2008; 205(12):2763–2779.
71.
HaaseAT: Perils at mucosal front lines for HIV and SIV and their hosts. Nature reviews. Immunology, 2005; 5(10):783–792.
72.
BrenchleyJM, SchackerTW, RuffLE, et al.: CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med, 2004; 200(6):749–759.
73.
HerbeuvalJP, HardyAW, BoassoA, et al.: Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci USA, 2005; 102(39):13974–13979.
74.
WiersmaVR, de BruynM, HelfrichW, and BremerE: Therapeutic potential of galectin-9 in human disease. Med Res Rev, 2013; 33(,Suppl 1):E102–126.
75.
KaredH, FabreT, BedardN, et al.: Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog, 2013; 9(6):e1003422.
76.
NdhlovuLC, SinclairE, EplingL, et al.: IL-2 immunotherapy to recently HIV-1 infected adults maintains the numbers of IL-17 expressing CD4+ T (T(H)17) cells in the periphery. J Clin Immunol, 2010; 30(5):681–692.
77.
NdhlovuLC, LooCP, SpottsG, et al.: FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection. J Leuk Biol, 2008; 83(2):254–262.
78.
NdhlovuLC, ChapmanJM, JhaAR, et al.: Suppression of HIV-1 plasma viral load below detection preserves IL-17 producing T cells in HIV-1 infection. AIDS, 2008; 22(8):990–992.
79.
PasternakAO, JurriaansS, BakkerM, et al.: Cellular levels of HIV unspliced RNA from patients on combination antiretroviral therapy with undetectable plasma viremia predict the therapy outcome. PLoS One, 2009; 4(12):e8490.
80.
LambotteO, BoufassaF, MadecY, et al.: HIV controllers: A homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis, 2005; 41(7):1053–1056.
81.
PetrovasC, MuellerYM, and KatsikisPD: Apoptosis of HIV-specific CD8+ T cells: An HIV evasion strategy. Cell Death Differ, 2005; 12(,Suppl 1):859–870.
82.
YanJ, SabbajS, BansalA, et al.: HIV-specific CD8+ T cells from elite controllers are primed for survival. J Virol, 2013; 87(9):5170–5181.
83.
SajadiMM, ConstantineNT, MannDL, et al.: Epidemiologic characteristics and natural history of HIV-1 natural viral suppressors. J Acquir Immune Defic Syndr, 2009; 50(4):403–408.
84.
HuntPW, BrenchleyJ, SinclairE, et al.: Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis, 2008; 197(1):126–133.
85.
HsuePY, DeeksSG, FarahHH, et al.: Role of HIV and human herpesvirus-8 infection in pulmonary arterial hypertension. AIDS, 2008; 22(7):825–833.
86.
PereyraF, PalmerS, MiuraT, et al.: Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis, 2009; 200(6):984–990.
87.
HatanoH, DelwartEL, NorrisPJ, et al.: Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol, 2009; 83(1):329–335.
88.
HuntPW, LandayAL, SinclairE, et al.: A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One, 2011; 6(1):e15924.
89.
HuntPW, BrenchleyJ, SinclairE, et al.: Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis, 2008; 197(1):126–133.
90.
ShashaD and WalkerBD: Lessons to be learned from natural control of HIV––Future directions, therapeutic, and preventive implications. Front Immunol, 2013; 4:162.
91.
DoitshG, CavroisM, LassenKG, et al.: Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell, 2010; 143(5):789–801.
92.
DoitshG, GallowayNL, GengX, et al.: Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature, 2014; 505(7484):509–514.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
