Plasma (1 → 3)-β-d-glucan and suPAR levels correlate with neurocognitive performance in people living with HIV on antiretroviral therapy: a CHARTER analysis

Abstract

Despite antiretroviral therapy (ART), people living with HIV (PLWH) have higher rates of non-AIDS disorders, such as neurocognitive (NC) impairment (NCI) than the general population. (1-3)-β-D-Glucan (BDG) is a fungal cell wall component which serves as a biomarker for gut barrier integrity failure and microbial and fungal translocation. The primary objective of this study was to determine whether higher plasma and cerebrospinal fluid (CSF) levels of BDG and suPAR were associated with NCI in PLWH. Paired blood and CSF samples were collected cross-sectionally from 61 male adult PLWH on ART (95% virally suppressed) who underwent a detailed NC assessment as part of the prospective CHARTER study between 2005 and 2015. BDG and soluble urokinase plasminogen activator receptor (suPAR) were measured in frozen blood and CSF samples while soluble CD14 (sCD14), intestinal fatty acid binding protein (IFABP), and CD4/CD8 ratio were measured in blood only. Spearman's rho correlation analysis assessed associations between BDG, other biomarkers, and NC performance. Median BDG levels were 18 pg/mL in plasma (range 2-60 pg/mL) and 20 pg/mL in CSF (range 0-830 pg/mL). Higher levels of plasma BDG were associated with worse NC performance (Spearman's rho = − 0.32; p = 0.013) and with the presence of NCI (p = 0.027). A plasma BDG cutoff of > 30 pg/mL was 30% sensitive and 100% specific for NCI. After adjusting for age, higher plasma suPAR levels were also associated with worse NC performance (p < 0.01). No significant associations were observed between the remaining biomarkers and the NC variables. Plasma levels of BDG and age-adjusted suPAR may be new biomarkers for the detection of NCI in PLWH on suppressive ART.

Editorial: HIV-Associated Immune Activation and Persistent Inflammation

“…Bacteria and fungi are the two most abundant populations of the gut microbiome. While bacterial translocation has been a focus of HIV research for a number of years, fungal translocation recently came into focus as a driver of immune activation, persistent inflammation, and non-AIDS events (7)(8)(9)(10)(11)(12). A review included in this supplement evaluated recent literature to untangle the respective roles of circulating lipopolysaccharide (LPS) and (1->3)-B-D-Glucan (BDG), which are major components of bacterial and fungal cell walls respectively and established biomarker of bacterial and fungal translocation (Ramendra et al).…”

Breakthrough invasive fungal infections: Who is at risk?

“…Besides disruption of the mucosal barrier (eg caused by persistent inflammation, hypoperfusion or oxidative stress), major risk factors for fungal translocation also include alteration of the normal GI microflora and impaired host defence 109. Multiple different underlying diseases that are associated with one of these conditions may contribute to fungal translocation, including sepsis,110,111 kidney disease, liver cirrhosis 112 and HIV infection [113][114][115][116][117]. The effects of chemotherapy on fungal organisms themselves have been theorised to also play a role in translocation.…”

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

“…Circulating BDG is currently used for the clinical diagnosis of Candida, Aspergillus, and Pneumocystis jirovecii invasive infections [18]. Recently, we and others have found that plasma levels of BDG are associated with epithelial gut damage and risk of developing inflammatory non-AIDS comorbidities in PLWH without invasive fungal infection (IFI) [12][13][14][18][19][20][21][22]. These findings show converging evidence that BDG is a clinically significant fungal translocation marker in PLWH.…”

“…LPS is a bacterial cell wall polysaccharide and is a well-known inducer of innate immune activation [11]. Besides bacterial translocation, there is increasing awareness regarding fungal translocation [12][13][14][15]. Fungi contribute greatly to opportunistic infections in PLWH, including Pneumocystis jirovecii in the respiratory tract and Candida albicans in the gastrointestinal tract [16].…”