Soluble T-Cell Immunoglobulin Mucin Domain-3 Is Associated With Hepatitis C Virus Coinfection and Low-Grade Inflammation During Chronic Human Immunodeficiency Virus Infection

Hedda Hoel; Thor Ueland; Malene Hove-Skovsgaard; Hans Jakob Hartling; Marco Gelpi; Thomas Benfield; Henrik Ullum; Annika E Michelsen; Pål Aukrust; Susanne Dam Nielsen; Marius Trøseid

doi:10.1093/ofid/ofaa033

Soluble T-Cell Immunoglobulin Mucin Domain-3 Is Associated With Hepatitis C Virus Coinfection and Low-Grade Inflammation During Chronic Human Immunodeficiency Virus Infection

Open Forum Infect Dis. 2020 Jan 29;7(2):ofaa033. doi: 10.1093/ofid/ofaa033. eCollection 2020 Feb.

Authors

Hedda Hoel^{1

2

3}, Thor Ueland^{1

2}, Malene Hove-Skovsgaard^{4

5}, Hans Jakob Hartling^{4

5}, Marco Gelpi^{4

5}, Thomas Benfield^{6

7}, Henrik Ullum⁸, Annika E Michelsen^{1

2}, Pål Aukrust^{1

2

9}, Susanne Dam Nielsen^{4

5

7}, Marius Trøseid^{1

2

9}

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Medical Department, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁴ Department of Infectious diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵ Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Infectious Diseases, Amager Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark.
⁹ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Abstract

Background: In well treated human immunodeficiency virus infection (HIV), there is a residual immune activation and immune exhaustion that may contribute to increased risk of comorbidities. T-cell immunoglobulin mucin domain-3 (Tim-3) is an inhibitory molecule involved in HIV-associated T-cell dysfunction. The Tim-3 can be cleaved to soluble Tim-3 (sTim-3) that may serve as a soluble marker of immune exhaustion.

Methods: We measured sTim-3 with enzyme-linked immunosorbent assay DuoSets in a cross-sectional cohort of 1010 people with HIV (PWH) on antiretroviral therapy (ART), and 76 controls from the Copenhagen Co-Morbidity in HIV Infection (COCOMO) study, and in a longitudinal cohort of 60 PWH before and during ART.

Results: In the cross-sectional cohort, levels of sTim-3 were elevated in PWH on ART compared with controls, especially in hepatitis C virus (HCV)-coinfected individuals, and were associated with HCV viremia and inflammation. In the longitudinal cohort, pretreatment sTim-3 correlated with HIV viral load and decreased after ART initiation. Pretreatment sTim-3 correlated inversely with CD4 counts, but it did not predict immunological response in multivariable analyses.

Conclusions: Levels of sTim-3 decreased after ART initiation. In a cross-sectional cohort, levels of sTIM-3 were higher in PWH than in controls and were independently associated with HCV coinfection and high-sensitivity C-reactive protein, representing a potential link between immune exhaustion, inflammation, and risk of comorbidities.

Keywords: HIV; Tim-3; hepatitis C; immune exhaustion; soluble.