Plasma Levels of C-Type Lectin REG3α and Gut Damage in People With Human Immunodeficiency Virus

Abstract

Background: Regenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH.

Methods: Plasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)-uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers.

Results: Cross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH.

Conclusions: Plasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.

Keywords: HIV; REG3α; gut damage; inflammation; microbial translocation.

Figure 1.

Plasma levels of regenerating islet-derived protein 3α (REG3α) were elevated over the course of human immunodeficiency virus (HIV) infection. A, Plasma REG3α levels during early and chronic infection compared to elite controllers (ECs) and uninfected controls. Early HIV without antiretroviral therapy (ART^–) (n = 51), chronic HIV without ART (n = 22), chronic HIV with ART (ART⁺; n = 66), ECs (n = 30), and controls (n = 30), Kruskal–Wallis test. B, Plasma intestinal fatty acid binding protein (I-FABP) levels in early HIV infection without ART (n = 56), chronic HIV without ART (n = 22), chronic HIV with ART (n = 71), ECs (n = 30), and controls (n = 30), Kruskal–Wallis test. Longitudinal analysis showed that plasma levels of REG3α (C) but not I-FABP levels (E) increased over 24 months in people living with HIV (PWH) without ART (n = 12), Wilcoxon test. Longitudinal analysis showed that plasma levels of REG3α (D) but not I-FABP (F) decreased in PWH after 24 months on ART (n = 10), Wilcoxon test. ns, not significant.

Figure 2.

Plasma levels of regenerating islet-derived protein 3α (REG3α) correlated with markers of disease progression. A, Plasma REG3α levels correlated with human immunodeficiency virus (HIV) viral load in participants with early HIV and chronic HIV without ART (n = 72). B, Plasma REG3α inversely correlated with CD4 T-cell count (B) and CD4:CD8 ratio (C) in most participants (n = 161). D, Plasma REG3α was associated with anti-cytomegalovirus (CMV) immunoglobulin G (IgG) titer in people living with HIV (n = 82). Spearman test was used for correlations. Light blue indicates early HIV infection, orange indicates chronic HIV infection without ART, red indicates chronic HIV infection with ART, and purple indicates elite controllers.

Figure 3.

Plasma levels of regenerating islet-derived protein 3α (REG3α) were associated with markers of epithelial gut damage and microbial translocation. A, Plasma levels of REG3α correlated with plasma intestinal fatty acid binding protein (I-FABP) levels in all people living with human immunodeficiency virus (PWH; n = 165). B, Plasma levels of REG3α were correlated with plasma levels of lipopolysaccharide (LPS; n = 163). C, Plasma levels of REG3α correlated with plasma levels of soluble CD14 (sCD14) in PWH (n = 109). Spearman test was used for correlations. Light blue indicates early human immunodeficiency virus (HIV) infection, orange indicates chronic HIV infection without antiretroviral therapy (ART), red indicates chronic HIV infection with ART, and purple indicates elite controllers.

Figure 4.

Plasma levels of regenerating islet-derived protein 3α (REG3α) were associated with markers of myeloid and lymphoid activation. Plasma levels of REG3α were correlated with plasma levels of interleukin 6 (IL-6; A) and interleukin 8 (IL-8; B) (n = 168). Plasma levels of REG3α correlated with indoleamine-2,3-dioxygenase (IDO-1) activity as REG3α levels were positively associated with the kynurenine-to-tryptophan (Kyn/Trp) ratio (C) in a subset of people living with human immunodeficiency virus (HIV) (n = 88). Spearman test was used for correlations. Light blue indicates early HIV infection, orange indicates chronic HIV infection without antiretroviral therapy (ART), red indicates chronic HIV infection with ART, and purple indicates elite controllers.