Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection G. Harcourt, 1 S. Hellier, 2 M. Bunce, 3 J. Satsangi, 2 J. Collier, 2 R. Chapman, 1 R. Phillips 1 and P. Klenerman 1 1 Nuf®eld Department of Medicine, 2 Department of Gastroenterology, John Radcliffe Hospital, Oxford, and 3 Tissue Typing, Churchill Hospital, Oxford, UK Received 1,2 November 2000; accepted for publication 1,2 December 2000 INTRODUCTION Hepatitis C virus (HCV) is thought to affect about 170 mil- lion people worldwide [1]. In the majority of those exposed, a persistent infection is set up and in a variable proportion, this leads on to hepatic ®brosis, cirrhosis and liver failure. In some patients, treatment with interferon-a and ribavirin can clear virus from blood and interrupt progression of disease but, through a combination of virological and immunologi- cal factors, this is only successful in about 50% of cases [2,3]. The immunological and virological mechanisms which, overall, lead to persistence rather than clearance and treatment success rather than failure are incompletely understood. It is likely that cellular immune responses are involved in the control of viral replication, both from work in HCV and in other viral systems [4±7]. There is evidence from studies of HCV-infected patients that early broadly reactive (`multispeci®c') CD4+ T helper responses are associated with clearance of virus from blood [5,8,9]. Responses to particular viral antigens such as a core or a conserved region of NS3 have been pro- posed as particularly protective, although there is a lack of consensus as to which epitopes are important in protection [5,10±12]. Loss of CD4+ T-cell responses may be tem- porally associated with recrudescence of virus in those who initially become PCR negative 3 after infection. The presence of CD4+ T helper responses in those who have had a sustained spontaneous clearance in the long term (i.e. over 20 years or more), as opposed to immediately postinfection, has not been fully resolved. This may be of relevance as we found that even in those with a sustained clearance, CD8+ T lymphocyte responses were signi®- cantly diminished in this group compared with in the postacute period [4]. The breadth of the response is likely to be important in both CD4+ and CD8+ T lymphocyte responses. A response against multiple epitopes reduces the likelihood of escape through antigenic variation. Mutation within class I and class II restricted epitopes may lead to loss of peptide binding or T-cell recognition, T-cell antagonism and distortion of T-cell function, as has been shown in various viral infections including HCV [14,15]. In studies of CD8+ T lymphocyte responses, responses against more than one of the tested Abbreviations: HCV, hepatitis C virus; PBMC, peripheral blood mononuclear cells. Correspondence: Dr Paul Klenerman, Nuf®eld Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9 DU, UK. E-mail: klener@molbiol.ox.ac.uk Journal of Viral Hepatitis, 2001, 8, 174±179 Ó 2001 Blackwell Science Ltd SUMMARY. Hepatitis C virus (HCV) infection is very common worldwide, but has a broad range of outcomes. A minority of patients are able to clear infection spontane- ously, and this is thought to be due to the emergence and maintenance of effective cell-mediated immunity, partic- ularly CD4+ T lymphocyte responses. Furthermore, genetic studies have indicated that HLA class II genotype strongly in¯uences the outcome of infection. We have therefore investigated the in¯uence of the protective HLA class II haplotype (DQB1*0301, which is in tight linkage disequi- librium with DRB1*1101) on the CD4+ T lymphocyte responses to HCV. We observe a strong association between this genotype and maintenance of a multispeci®c CD4+ T helper response. The effect on T helper responses was also maintained after combination interferon-a/ribavirin ther- apy, although the latter in¯uenced the pattern of viral antigens to which patients responded. This is the ®rst disease in which an association of HLA genotype with clinical out- come has been linked to an alteration of the immunological phenotype. The selection of protective peptides in those with the favourable HLA class II genotype may point in the direction of suitable vaccine candidates. Keywords: CD4 responses, hepatitis C virus, HLA class II.