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Background/aims: Community-based assessment and management of chronic liver disease (CLD) in people who are homeless (PWAH) remains poorly described. We aimed to determine prevalence/predictors of chronic liver disease (CLD) in PWAH and assess performance of non-invasive hepatocyte fibrosis and injury markers. Methods: The Vulnerable Adult LIver Disease (VALID) study provided a “one-stop” liver service based at homeless hostels. Our primary outcome was the prevalence of clinically significant hepatic fibrosis (CSHF) (liver stiffness measurement (LSM) > 8kPa). Results: Total individuals recruited were 127, mean+SD age 47+9.4 years, 50% (95% CI 41%-59%) and 39% (95% CI 31%- 48%) having alcohol dependence and a positive HCV RNA respectively. CSHF was detected in 26% (95% CI 17%-35%), independent predictors being total alcohol unit/week (OR 1.01, 95% CI 1.00-1.02, p=0.002) and HCV RNA positivity (OR 2.93, 95% CI 1.12-7.66, p=0.029). There was moderate agreement between LSM and Enhanced Liver Fibrosis (ELF) score (kappa 0.536, p8kPa. Those with CSHF had significantly higher levels of IFN-γ (p=0.002), IL-6 (p=0.001), MMP-2 (p=0.006), ccCK-18 (p95%. Direct acting antiviral (DAA) treatment completion was 93% (95% CI 77%-99%), sustained virological response (SVR) being 83% (95% CI 64%-94%). Conclusion: There is a significant liver disease burden from HCV and alcohol in PWAH. Non-invasive hepatocyte fibrosis and injury markers can help in identifying such individuals in the community. Despite a challenging cohort, excellent service uptake and high DAA-based SVRs can be achieved.

Lamia Heikal,1 Pietro Ghezzi,1 Manuela Mengozzi,1 Blanka Stelmaszczuk,2 Martin Feelisch,2 Gordon AA Ferns1 1Brighton and Sussex Medical School, Falmer, Brighton, 2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton, UK Abstract: The cytoprotective effects of erythropoietin (EPO) and an EPO-related nonerythropoietic analog, pyroglutamate helix B surface peptide (pHBSP), were investigated in an in vitro model of bovine aortic endothelial cell injury under normoxic (21% O2) and hypoxic (1% O2) conditions. The potential molecular mechanisms of these effects were also explored. Using a model of endothelial injury (the scratch assay), we found that, under hypoxic conditions, EPO and pHBSP enhanced scratch closure by promoting cell migration and proliferation, but did not show any effect under normoxic conditions. Furthermore, EPO protected bovine aortic endothelial cells from staurosporine-induced apoptosis under hypoxic conditions. The priming effect of hypoxia was associated with stabilization of hypoxia inducible factor-1α, EPO receptor upregulation, and decreased Ser-1177 phosphorylation of endothelial nitric oxide synthase (NOS); the effect of hypoxia on the latter was rescued by EPO. Hypoxia was associated with a reduction in nitric oxide (NO) production as assessed by its oxidation products, nitrite and nitrate, consistent with the oxygen requirement for endogenous production of NO by endothelial NOS. However, while EPO did not affect NO formation in normoxia, it markedly increased NO production, in a manner sensitive to NOS inhibition, under hypoxic conditions. These data are consistent with the notion that the tissue-protective actions of EPO-related cytokines in pathophysiological settings associated with poor oxygenation are mediated by NO. These findings may be particularly relevant to atherogenesis and postangioplasty restenosis. Keywords: erythropoietin, pyroglutamate helix B surface peptide, scratch assay, proliferation, migration, apoptosis

Interleukin (IL)-12, especially in the presence of neutralizing anti-IL-4 monoclonal antibodies, primed CD45RO(-) T clones for high CCL3/macrophage-inflammatory protein-lot (MIP-1alpha) and CCL4/MIP-1beta levels. In CD4(+) and CD8(+) clones from two patients deficient for IL-12Rbeta1 (IL-12Rbeta1(-/-)), production of CCL3/MIP-1alpha and CCL4/MIP-1beta was defective. CD4(+) clones from two patients deficient for interferon-gamma (IFN-gamma) R1 (IFN-gammaR1(-/-)) produced somewhat decreased CCL4/MIP-1beta levels. IL-12 failed to prime CD4(+) or CD8(+) healthy clones for high CCL5/regulated on activation, normal T expressed and secreted (RANTES) production, although its secretion was impaired in CD4(+) clones from IL-12Rbeta1(-/-) and IFN-gammaR1(-/-) patients. CCR5 surface expression was up-regulated in resting peripheral blood mononuclear cells and CD4(+) clones from both kinds of patients, rendering them more susceptible to CCR5-dependent (R5) HIV-1 infection. Neutralization of IFN-gamma increased CCR5 expression and decreased CC-chemokine secretion by CD4(+) clones from healthy and IL-12Rbeta1(-/-) individuals, suggesting an IFN-gamma-dependent control of CCR5 expression. These data provide the first documented analysis of chemokine secretion and chemokine receptor expression on T cells from IL-12 and IFN-gamma receptor-deficient patients and dissect the role of IL-12 and IFN-gamma on inducing inflammatory chemokine secretion and down-regulating CCR5 expression in human T cells.

Macrophage-derived chemokine (MDC) has been reported to inhibit different HIV-1 strains in activated peripheral blood mononuclear cells (T cell blasts), although other investigators have not confirmed these findings. Here we demonstrate that MDC inhibits the replication of CCR5-dependent (R5) HIV-1BaLin monocyte-derived macrophages (MDM), but not in T cell blasts, although with variable potency depending on donor variability. Analysis of HIV-1BaLproviral DNA synthesis in MDM indicated that the suppressive effect of MDC did not involve inhibition of early events such as entry or reverse transcription. Finally, an inverse correlation was observed between the levels of endogenous MDC secreted by uninfected MDM of different donors and the efficiency of different HIV strains, including two primary isolates with different coreceptor usage, to replicate in these cells. Thus, MDC represents an example of a chemokine inhibiting HIV replication in macrophages acting at one or more postentry levels in the virus life cycle.

U937 cell clones which sustain efficient or poor replication of human immunodeficiency virus type 1 (HIV-1) (referred to herein as plus clones and minus clones, respectively) have been previously described. 1,25-Dihydroxyvitamin D3 (vitamin D3) potently induced HIV-1 replication and proviral DNA accumulation in minus clones but not in plus clones. Vitamin D3 did not induce NF-KB activation but selectively upregulated CXCR4 expression in minus clones. The CXCR4 ligand stromal-cell derived factor-1 induced Ca2+ fluxes and inhibited both constitutive and vitamin D3-enhanced HIV replication in minus clones.