Plasma proteomic profiles of patients with HIV infection and coinfection with hepatitis B/C virus undergoing anti­retroviral therapy.

Chronic liver disease is becoming a leading cause of illness and mortality in patients living with human immunodeficiency virus (HIV; PLWH) undergoing suppressive anti-retroviral therapy. Its primary etiology is coinfection with hepatitis B and C virus (HBV and HCV, respectively). Chronic liver inflammation and fibrosis can potentially lead to the development of hepatocellular carcinoma (HCC). Therefore, monitoring of the disease progression in PLWH is required. The present study aimed to explore plasma protein profiles of PLWH and those coinfected with HBV and HCV using shotgun proteomics. HIV-monoinfected, HIV/HBV-coinfected, HIV/HCV-coinfected and uninfected control individuals were recruited. Patients in the three virus-infected groups had significantly higher levels of liver fibrosis indices (fibrosis-4 score and aspartate aminotransferase to platelet ratio index) compared with the control group. Liquid chromatography-tandem mass spectrometry analysis of plasma samples identified 1,074 proteins that were differentially expressed, where subsequent partial least squares-discriminant analysis model demonstrated clear clustering of proteomes from the four sample groups; 18 proteins that were significantly differentially expressed. Heatmap analysis identified two main groups of proteins, six proteins being upregulated only in the HIV/HBV-coinfection group and 10 proteins downregulated in all three virally infected groups. STITCH 5.0 analysis predicted an interaction network containing two identified proteins in the latter group, specifically ubiquitin interaction motif-containing 1 (UIMC1) and haptoglobin (HP), which are part of the profibrogenic TGF-1ß/SMAD, inflammatory TNF and tumor suppressor BRCA1 pathways. Expression levels of UIMC1 and HP were significantly lower in HIV-infected groups compared with those in uninfected controls. Altogether, these proteomics data provide protein expression profiles potentially associated with HIV infection and coinfection with HBV/HCV, which may be applied to predict progression to advanced liver disease or HCC in PLWH.

Distribution and Clinical Significance of Hepatitis B virus A1762T/G1764A Double Mutation in Chronic Hepatitis B Patients: A Cross-Sectional Study.

BACKGROUND: Chronic hepatitis B (CHB) is well-known as a major risk for liver cirrhosis and hepatocellular carcinoma (HCC). The A1762T/G1764A double mutation in the hepatitis B virus genome affects the production of HBe antigen and is established as a predictive marker for progression to HCC. Thus, this study aimed to investigate the prevalence and clinical significance of the mutation in Thai CHB patients. METHODS:  A cross-sectional study was conducted in 78 Thai CHB patients who were assessed for hepatitis B profiles, HBsAg, HBeAg and anti-HBeAg, transaminitis, liver fibrosis defined by FIB-4 (FIB-4) score and AST to platelet ratio index (APRI), alpha-fetoprotein (AFP) and active hepatitis B status. HBV A1762T/G1764A mutation was examined by SYBR Green I Real-time PCR. Chi-square and Mann-Whiney U tests were performed to determine the association between the mutation and variables. RESULTS: The prevalence of patients infected with the A1762T/G1764A mutation was 44.9%. The mutation was associated with HBeAg status (p=0.027) and HBsAg levels (p=0.008), transaminitis (p=0.011), and active hepatitis B (p=0.037), but not liver fibrosis markers, FIB-4 score and APRI, and AFP. Binary logistic regression identified the mutation as a predictive factor of active hepatitis B (OR 3.5, 95%CI, 1.1-11.3, p=0.037). Patients infected with the mutant exhibited significantly higher levels of HBsAg (p=0.011) and HBV viral load (p=0.047), but lower levels of HBeAg (p=0.12) than those infected with the wild-type HBV. CONCLUSION: The data indicate the high prevalence of the A1762T/G1764A mutation and its significant association with the severity of Thai CHB patients and the HBV mutation is proposed as a predictive marker of active hepatitis B status in CHB patients.

Lack of Association between IFN-γ, CXCL10 and TGF-ß1 Gene Polymorphisms and Liver Complication in HIV-infected Thais.

OBJECTIVE: Chronic liver disease has become a leading cause of illness and death in people living with HIV and the production of the cytokines IFN-γ and TGF-ß1, and chemokine CXCL10 during chronic inflammation contributes to liver disease progression in HIV patients under long-term anti-retroviral therapy. This study aimed to examine association of IFN-γ +874T/A, CXCL10 G-201A and C-1596T, and TGF-ß1 -509C/T single nucleotide polymorphisms (SNPs) with liver complications in the HIV-infected Thais. METHODS: A cross-sectional study was conducted in 200 Thai HIV patients who were evaluated for transaminitis and significant liver fibrosis by fibrosis-4 score (FIB-4), and genotypes for IFN-γ +874T/A, CXCL10 G-201A and C-1596T, and TGF-ß1 -509C/T SNPs using PCR-based methods. RESULT: There were high rates of transaminitis (30.1%) and significant liver fibrosis assessed by FIB-4 score > 1.45 (18.8%) in this group of patients, mostly under anti-retroviral therapy (73.0%). The genotypes and alleles of IFN-γ +874T/A, CXCL10 G-201A and C-1596T, and TGF-ß1 -509C/T SNPs were not associated with either transaminitis or FIB-4 score > 1.45 (p > 005). Logistic regression analysis identified age and gender as risk factors, and CD4+ cell count higher than 350 cells/ul as a protective factor of liver fibrosis in this study group. CONCLUSION: The IFN-γ +874T/A, CXCL10 G-201A and C-1596T, and TGF-ß11 -509C/T SNPs were not significantly associated with liver complication in HIV-infected Thais, mostly under ART.

Genotypic and allelic distribution of IFN-γ +874T/A and TGF-ß1 -509C/T single-nucleotide polymorphisms in human immunodeficiency virus-infected Thais.

Advances in antiretroviral therapy (ART) have led to a decrease of acquired immunodeficiency syndrome (AIDS)-related mortality, and an increase of non-AIDS illnesses in people living with HIV (PLWH). Risks for HIV-related chronic inflammation leading to non-AIDS illnesses in PLWH have been increasingly clarified including immunogenetic factors. This study aimed to examine distribution of genotypic and allelic frequencies of the well-characterized interferon-γ (IFN-γ) +874T/A and transforming growth factor-ß1 (TGF-ß1) -509C/T single nucleotide polymorphisms (SNPs) in Thai PLWH. The cross-sectional study was conducted in 191 Thai HIV patients. Most patients were under ART (74.3%) and maintained a relatively high median of CD4+  cell count (364.5 [5-1601] cells/µl). The frequencies of IFN-γ +874T/A  SNP genotypes were 9.0% AA, 38.3% AT, and 52.7% TT and those of the SNP alleles were 28.1% A and 71.9% T. The rates of TGF-ß1-509C/T SNP genotypes were 15.7% CC, 44.0% CT, and 40.3% TT and those of the SNP alleles were 37.7% C and 62.3% T. The more frequent TT genotypes and T allele of the IFN-γ +874T/A SNP, and relatively more prevalent TT and CT genotypes and T allele of TGF-ß1 -509C/T SNP were potentially associated with disease progression to non-AIDS complication in Thai PLWH and required further investigation. This study provides the immunogenetic data potentially supporting mechanisms for chronic immune activation in PLWH under long-term suppressive ART.