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.

The Bacterium Akkermansia muciniphila: A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation

“…REG3α is an antimicrobial peptide secreted by intestinal Paneth cells into the gut lumen and upon gut damage, translocates into the blood (14). We observed that these two gut damage markers were correlated with HIV disease progression, microbial translocation and immune activation in PLWH (14). These findings point to the leaky gut as a significant contributor to chronic inflammation and non-AIDS comorbidities in PLWH.…”

“…I-FABP, an intracellular protein constitutively expressed in enterocytes, is released upon cell death and subsequently detected in the blood (96,97). REG3α is an antimicrobial peptide secreted by intestinal Paneth cells into the gut lumen and upon gut damage, translocates into the blood (14). We observed that these two gut damage markers were correlated with HIV disease progression, microbial translocation and immune activation in PLWH (14).…”

“…Our group and others have shown that LPS and BDG translocation are correlated with immune dysfunction in PLWH and increased risk of non-AIDS comorbidities (91)(92)(93)(94). Moreover, we and others have evaluated circulating intestinal fatty acid binding protein (I-FABP) and regenerating isletderived protein-3α (REG3α) as two gut damage markers in PLWH (14,95). I-FABP, an intracellular protein constitutively expressed in enterocytes, is released upon cell death and subsequently detected in the blood (96,97).…”

“…Antiretroviral therapy (ART) has transformed the lives of PLWH by rapidly controlling viral replication and allowing CD4 recovery, reducing morbidity and mortality. However, despite controlling viral load and CD4 Tcell count, long-term ART reduces but does not normalize gut dysbiosis, microbial translocation, immune activation and inflammation (12)(13)(14). In addition to HIV itself, coinfection with cytomegalovirus or viral hepatitis, leaky gut and microbial translocation also lead to inflammation which has been associated with the risk of non-AIDS comorbidities (13,(15)(16)(17)(18).…”

Daily variations of gut microbial translocation markers in ART-treated HIV-infected people

“…Circulating intestinal fatty acid binding protein (I-FABP) and regenerating islet-derived protein-3α (REG3α) are two validated gut damage markers in PLWH [23,24]. I-FABP, an intracellular protein constitutively expressed in enterocytes, is released upon cell death and subsequently detected in the blood in inflammatory bowel diseases (IBD) and HIV infection [25,26].…”