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Hepatitis C virus (HCV) persists in ~80% of infected individuals. The mechanisms involved in HCV persistence and pathogenesis are not fully understood. The E2 envelope glycoprotein of HCV has been shown to bind to CD81, and it is hypothesised that E2 cross-linking of CD81 may have immunomodulatory effects. This thesis addressed the interaction of E2 with CD81 and other putative receptors on peripheral blood mononuclear cell (PBMC) subsets, and the potential for CD81 cross-linking to modulate innate responses. Soluble truncated E2 glycoproteins were produced from several HCV genotype 1a and 1b strains, and their binding to PBMC subsets was investigated. CD81 was detected on all PBMC subsets, although expression levels on different cell types varied. By contrast, expression of SR-BI (another E2-binding protein) was restricted to monocytes and dendritic cells (DCs). H77c E2 showed a high level of binding to PBMCs, with binding to cell subtypes correlating with their level of CD81 expression. Other E2s showed a similar pattern of interaction with PBMC subtypes, but bound less well to all cell subsets. The effect of antibody-mediated cross-linking of CD81 on NK cell and DC responses was investigated. No specific effect of CD81 ligation was seen on the response of NK cells to CD16 or cytokine stimulation. However, CD81 cross-linking specifically inhibited MICA-stimulated NK cell activation. Investigation of the effect of CD81 cross-linking on the response of monocyte-derived DCs to LPS, poly(I:C) and CD40 ligation did not reveal a role for CD81 in modulating DC responses to these stimuli, a finding confirmed by examining the response of bone-marrow derived DCs from CD81 deficient mice to these stimuli. If E2-CD81 interaction mediates immunomodulatory effects in vivo, the difference observed in the binding level of E2s from different HCV strains to PBMCs suggests that this may constitute one of the determinants of viral persistence/pathogenesis.