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Metabolic complications relating to complex effects of viral and immune-mediated mechanisms are now a focus of clinical care among persons living with human immunodeficiency virus (PLHIV), and obesity is emerging as a critical problem. To address knowledge gaps, the US National Institutes of Health sponsored a symposium in May 2018 entitled "Obesity and Fat Metabolism in HIV-infected Individuals." Mechanisms relating to adipose dysfunction and fibrosis, immune function, inflammation, and gastrointestinal integrity were highlighted as contributors to obesity among PLHIV. Fibrotic subcutaneous adipose tissue is metabolically dysfunctional and loses its capacity to expand, leading to fat redistribution, including visceral obesity and ectopic fat accumulation, promoting insulin resistance. Viral proteins, including viral protein R and negative regulatory factor, have effects on adipogenic pathways and cellular metabolism in resident macrophages and T cells. HIV also affects immune cell trafficking into the adipose compartments, with effects on adipogenesis, lipolysis, and ectopic fat accumulation. Key cellular metabolic functions are likely to be affected in PLHIV by gut-derived cytokines and altered microbiota. There are limited strategies to reduce obesity specifically in PLHIV. Enhancing our understanding of critical pathogenic mechanisms will enable the development of novel therapeutics that may normalize adipose tissue function and distribution, reduce inflammation, and improve insulin sensitivity in PLHIV., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

Background: Obese subjects with chronic hepatitis C virus (HCV) infection have more rapidly progressive liver disease. Objective In this study, we aimed to compare the hepatic cytokine and chemokine profiles in obese and lean subjects with chronic HCV infection using qRT-PCR and immunohistochemistry., Methods: Liver biopsies from 55 subjects were studied, including 20 with chronic hepatitis C, 25 with non-alcoholic fatty liver disease and 10 subjects with non-diseased liver., Results: Compared to the control groups, the liver injury in chronic hepatitis C was characterised by increased expression of several T-helper-1 cytokines including interferon-gamma and tumour necrosis factor-alpha, and chemokines such as RANTES, IP-10 and MCP-1. In particular, in comparison with lean (BMI or=30 kg/m(2)) HCV infected subjects had increased hepatic expression of interferon-gamma (p=0.004) and tumour necrosis factor-alpha (p<0.001), as well as increased expression of IP-10 (p=0.009) and MCP-1 (p<0.001). Localisation of these inflammatory chemokines revealed that in comparison to lean-HCV subjects, HCV infected liver from obese subjects exhibited significantly increased expression of IP-10 (p<0.001) and MCP-1 (p=0.02) in the inflammatory infiltrate of the portal tracts. In parallel, there was increased CD3 infiltration in the liver of obese-HCV subjects., Conclusions: The data provide important mechanistic information on the cause of hepatic injury in obese-HCV subjects including: (1) enhanced T helper-1 cytokine response patterns-to promote hepatocellular injury; (2) increased expression of the chemokines IP-10 and MCP-1 at both the mRNA and protein levels-to enhance inflammatory cell recruitment; (3) differing localisation of these chemokines within the liver of obese-HCV versus lean-HCV subjects-implying different inducing stimuli and; (4) increased CD3 expression in the liver of obese-HCV subjects-concordant with the increased expression of T cell chemoattractants.

Background & Aims In chronic hepatitis C virus infection ( CHC), expression of suppressor of cytokine signalling-3 ( SOCS3) has been shown to be associated with obesity and non-response to antiviral therapy. In this study, we aimed to determine the effect of SOCS3 induction on the cytokine response in patients receiving Pegylated interferon (Peg IFN) and ribavirin ( RBV) therapy. Methods Peripheral blood mononuclear cells (PBMC) collected at baseline and at 12 weeks from CHC patients receiving PegIFN/RBV therapy were examined for mRNA and protein SOCS3 expression. Immunological assays were employed to examine cytokine production. Results There was increased expression of SOCS3 in PBMC of non-responders at week 12 of therapy, when compared to treatment responders ( P = 0.0001). The expression of SOCS3 correlated with body mass index ( BMI) ( r = 0.54; P = 0.01). Patients with low SOCS3 expression at week 12 of therapy had lower HCV-specific IFN-γ production in enzyme-linked immunosorbent spot ( ELISpot) assays ( P = 0.01), and reduced ex-vivo production of the anti- HCV effector cytokines interleukin ( IL)-2 and tumour necrosis factor ( TNF)-α( P = 0.01 and P = 0.04 respectively). Analysis of serum cytokine levels revealed higher levels of IL-6 at week 12 in the high SOCS3 expression group ( P = 0.02) while IL-6 levels correlated with SOCS3 expression in the entire cohort ( P = 0.04). Ex-vivo studies confirmed that IL-6 induced SOCS3, and neutralisation of IL-6 reduced levels of SOCS3. Conclusion In subjects with increased BMI and non-response to antiviral therapy, the IL-6/ SOCS3 axis appears to play a crucial role in altering the anti- HCV-cytokine response associated with antiviral therapy. [ABSTRACT FROM AUTHOR]