Search

Background & Aims Neutralising antibodies (NAbs) play a key role in clearance of HCV. NAbs have been isolated and mapped to several domains on the HCV envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitope-specific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. Methods Using samples from 168 patients with primary HCV infection, the antibody responses targeted 2 immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains. Results No epitopes were uniquely targeted by clearers compared to those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralising domains. Conclusions This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains. Lay summary Neutralising antibodies will likely form a key component of a protective hepatitis C virus vaccine. In this work we characterise the predominant neutralising and non-neutralising antibody (epitope) targets in acute hepatitis C virus infection. We have defined the natural hierarchy of epitope immunodominance, and demonstrated that viral genotype can impact on this hierarchy. Our findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate.

performed using a non-targeted multiple platform methodologycombining ultrahigh performance liquid chromatography/tandemmass spectrometry (UHPLC/MS) and gas chromatography/massspectrometry (GC/MS). Metabolites were identified by automatedcomparison of ion features to a reference of chemical standardentries. Welch’s two-sample t-tests were used to identifybiochemicals that differed significantly between HCV infected andun-infected cells.Results: A total of 250 metabolites were detected and quantified,of which 73 were differentially regulated. At the 24-hour timepoint, there was a significant increase in a number of metabolitesinvolved in nucleotide synthesis and RNA replication. NAD levelswere also significantly increased along with several aminoacids. A number of lipid metabolic pathways were disruptedby HCV infection, resulting in an increase in cholesterol andsphingolipid levels, altered phospholipid metabolism and a possibledisruption in mitochondrial fatty acid transport. Fluctuations inmethylthioadenosine (MTA) levels were also noted, along withalterations in the glutathione synthesis pathway.Conclusions: These results suggest that elevated metabolism andaltered energy status are associated with early HCV infection. Thesefindings also provide new information on the effect HCV infectionhas on the disruption of lipid metabolism.813HEPATITIS C VIRUS-SPECIFIC CELLULAR IMMUNITY DOESNOT PROTECT AGAINST FUTURE HCV INFECTION IN ANTI-HCVNEGATIVE INJECTING DRUG USERSR. Sacks-Davis

127 HOMOZYGOSITY FOR THE PNPLA3/ADIPONUTRIN I148M POLYMORPHISM INFLUENCES LIVER FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE L. Valenti, A. Al-Serri, A.K. Daly, E. Galmozzi, R. Rametta, P. Dongiovanni, V. Nobili, E. Mozzi, G. Roviaro, E. Vanni, E. Bugianesi, M. Maggioni, A.L. Fracanzani, S. Fargion, C.P. Day. Internal Medicine, Universita degli Studi di Milano, Ospedale Policlinico IRCCS, Milan, Italy; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Liver Unit, Ospedale “Bambin Gesu, Rome, Vatican City; Surgery, Universita degli Studi di Milano, Milan, Gastroenterology, Universita di Torino, Turin, Pathology, Ospedale Policlinico IRCCS e San Paolo, Milan, Italy E-mail: luca.valenti@unimi.it