The hepatitis C virus persistence: Immunoglobulin mimicry by E2 protein

Abstract

The mechanisms by which hepatitis C virus (HCV) establishes persistent infection in the majority of infected individuals are unknown, but are thought to represent a complex interplay between viral diversity and host immunity. Currently, the most accepted hypothesis is that genetic variation within hypervariable region 1 (HVR1) of glycoprotein E2 may affect recognition by the immune system, leading to chronic infection. However, it can not explain how escape mutants evade subsequent immune recognition. Here, sequences within HCV E2 genes were analyzed during the course of primary HCV infections. We show that E2 possesses sequences that are homologous to sequences in the variable domains of human immunoglobulin (Ig) light chains in particular but also heavy chains and T cell receptors (TCR), and the degree of similarity of HVR1 to Ig types correlated with immune escape and persistence. In addition, recombinant E2 proteins (first 141 as or full length) were seen to bind to anti-human IgG antibodies, suggesting that N-terminal region of E2 is antigenically and structurally similar to human Ig variable domains. Overall, these data indicate that immunoglobulin mimicry by HCV E2 plays a significant role in viral immune escape and persistence.