REVIEW The bitter side of sweet: the role of Galectin-9 in immunopathogenesis of viral infections Shahzma Merani 1,2 , Wenna Chen 1,2 and Shokrollah Elahi 1,2 * 1 Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada 2 Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada SUMMARY In recent years, a critical role for β-galactoside-binding protein, Galectin-9 (Gal-9) has emerged in infectious disease, autoimmunity, and cancer. It is a ligand for T cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic viral infections. Gal-9 exerts its pivotal immunomodulatory effects by inducing apoptosis or suppressing effector functions via engagement with its receptor, Tim-3. Recent studies report elevation of circulating Gal-9 in humans infected with different viral infections. Interaction of soluble Gal-9 with Tim-3 expressed on the surface of activated CD4+ T cells renders them less susceptible to HIV-1 infection, while enhanced HIV infection occurs when Gal-9 interacts with a different receptor than Tim-3. This indicates the versatile role of Gal-9 in viral pathogenesis. For instance, higher expression of Tim-3 during chronic viral infection and elevation of plasma Gal-9 may have evolved to limit persistent immune activation and pathogenic T cells activity. In contrast, Gal-9 can suppress the effectiveness of immunity against viral infections. In agreement, Gal-9 knockout mice mount a more robust and vigorous virus-specific immune response in acute and chronic viral infections resulting in rapid viral clearance. In line with this observation, blocking Gal-9 signals to Tim-3-expressing T cells result in improved immune responses. Here we review the biological and immunological properties of Gal-9 in viral infections (HIV, HCV, HBV, HSV, CMV, influenza, and dengue virus). Manipulating Gal-9 signals may have immunotherapeutic potential and could represent an alternative approach for improving immune responses to viral infections/vaccines. Copyright © 2015 John Wiley & Sons, Ltd. Received: 2 December 2014; Revised: 4 February 2015; Accepted: 5 February 2015 INTRODUCTION Galectins are a family of sugar-binding proteins that possess one or two conserved carbohydrate recognition domains with beta-galactoside affinity [1]. Although most are widely distributed in mam- malian tissues, some have tissue restriction specific- ity, and to date, 15 of them have been identified. Within the immune system, galectins are expressed by virtually all immune cells, either constitutively or in an inducible manner, and are significantly up- regulated by B cells, T cells, natural killer (NK) cells, inflammatory macrophages, and regulatory T cells (Tregs) upon activation [2]. Galectins are abundantly expressed by innate and adaptive immune cells, which contribute in im- mune tolerance and inflammation. A number of galectins have been reported to contribute in host defense against infection; either by direct effects on the microorganisms (e.g. growth, adhesion, and entry) or by modulating the immune responses against them [2–6]. Herein, we discuss the role of Galectin-9 (Gal-9), a member of the galectin family, in viral infections. Galectin-9, a member of the β-galactoside- binding lectin family, was originally identified as an eosinophil chemoattractant [7]. It is expressed ubiquitously in different tissues and cells in humans and mice [8] and localized on the cell *Correspondence to: Dr. S. Elahi, Faculty of Medicine and Dentistry, University of Alberta, 7020L, Katz Group Centre for Pharmacy and Health Research, 11361-87th Ave NW, Edmonton, AB, T6G2E1, Canada. E-mail: elahi@ualberta.ca Abbreviations used CRDs, carbohydrate recognition domains; DC, dendritic cell; DENV, dengue virus; Gal-9, Galectin-9; HCMV, human CMV; iTreg, induced Treg; KO, knockout; MCMV, mouse CMV; NK Cell, natural killer cell; PDI, cell surface protein disulfide isomerase; TG, trigeminal ganglion; TIM-3, T cell immunoglobulin and mucin domain-containing mole- cule 3; Treg, regulatory T cells. Rev. Med. Virol. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/rmv.1832 Reviews in Medical Virology Copyright © 2015 John Wiley & Sons, Ltd.