Cannabinoid receptor 2-63 RR variant is independently associated with severe necroinflammation in HIV/HCV coinfected patients

Abstract

ObjectiveThis is the first study to analyze the impact of the rs35761398 variant of the CNR2 gene leading to the substitution of GLN (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with ARG (R) on the clinical presentation of chronic hepatitis in HIV/HCV coinfected patients.MethodsEnrolled in this study were 166 consecutive HIV/HCV coinfected patients, naïve for HCV treatment. A pathologist unaware of the patients’ condition graded liver fibrosis, necroinflammation (Ishak) and steatosis. All patients were screened for the CB2 rs35761398 polymorphism.ResultsOf the 166 HIV/HCV coinfected patients, 72.9% were males, 42.5% were infected with HCV-genotype-3 and 60.2% had been intravenous drug users. The median age was 40.6 years and the immunological condition good (median CD4+ cells/mm3 = 507, IQR: 398.0–669.5). Thirty-five (21.1%) patients were naive for ART and 131(78.9%) were on ART. The CB2-RR variant was detected in 45.8% of patients, QR in 38.6% and QQ in 15.7%. Patients with CB2-RR showed a necroinflammation score (HAI) ≥9 more frequently than those with CB2-QQ or CB2-QR (32.9% vs. 11.5% and 14.1%, respectively, p≤0.001). In the multivariate analysis, the CB2-RR variant (p = 0.03) and liver fibrosis were both identified as independent predictors of the entity of liver necroinflammation (p = 0.0001).ConclusionThis study shows interesting interplay between the CB2-RR variant and liver necroinflammation in chronic hepatitis patients with HIV/HCV coinfection, an observation of clinical value that coincides with the interest in the use of the CB2 agonists and antagonists in clinical practice emerging from the literature.

In vivo evidence that the cannabinoid receptor 2–63 RR variant is associated with the acquisition and/or expansion of HIV infection

“…This method has been extensively described in previous papers . Briefly, genomic DNA was extracted from peripheral whole blood with a DNA extraction kit (Roche Diagnostics).…”

“…One hundred and sixty-six consecutive anti-HIV-positive patients with HCV RNA-positive chronic hepatitis C and 186 consecutive HCV-monoinfected patients were enrolled in the study from 1993 to 2008 at the time at which they underwent their first liver biopsy at one of the two participating Units of Infectious Diseases, one in Milan and the other in Naples. These two centres have cooperated for a decade in numerous clinical investigations, applying the same clinical approach and laboratory methods [8,18,[23][24][25][26][27][28].…”

“…Several factors have been associated with a more rapid transition to the more severe stages of chronic hepatitis in hepatitis C virus (HCV)‐monoinfected patients, namely a longer duration of HCV infection, the TT variant of the interleukin‐28B polymorphism, the cannabinoid receptor (CB) 2–63 RR variant, coinfection with hepatitis B virus (HBV), insulin resistance, diabetes, high body mass index (BMI), alcohol abuse, drug addiction and immunosuppression of different aetiology . Liver fibrosis progression is accelerated in HIV/HCV‐coinfected patients and frequently leads to rapid hepatic decompensation even if HIV RNA is fully suppressed by antiretroviral therapy (ART) .…”

“…A polymorphism at codon 63 of the CB2 gene leads to the substitution of glutamine [Gln (Q)] with arginine [Arg (R)], with a consequent difference in protein polarization. In chronic hepatitis caused by HCV monoinfection, the CB2 QQ variant of the rs35761398 polymorphism of the CB2 gene has been found to be associated both with more severe liver necroinflammation and with the subsequent stage of a remission of necroinflammatory lesions , whereas in patients with HIV/HCV coinfection and chronic hepatitis, the CB2 RR variant was independently associated with more severe liver necroinflammation . To investigate this further, we evaluated the clinical impact of each variant of the rs35761398 polymorphism of the CB2 gene in two large series of patients with biopsy‐proven chronic hepatitis with HCV monoinfection or HIV/HCV coinfection.…”

CB2 receptor‐selective agonists as candidates for targeting infection, inflammation, and immunity in SARS‐CoV‐2 infections

“…Additionally, CB2 gene (CNR2) polymorphism shown to play a role in the immunopathogenesis associated with severe necroinflammation in patients with respiratory syncytial virus (Tahamtan et al, 2018), chronic hepatitis C (Coppola et al, 2014), childhood immune thrombocytopenic purpura (Rossi et al, 2011), and neuroinflammation in HIV/HCV co‐infected patients (Sagnelli et al, 2017). CB2R knockout mice showed increased susceptibility and vulnerability to influenza infection demonstrated the importance of CB2R in immunoregulation in respiratory viral infections (Kapellos et al, 2019).…”