TY - JOUR

T1 - Mutations within a conserved region of the hepatitis C virus E2 glycoprotein that influence virus-receptor interactions and sensitivity to neutralizing antibodies

AU - Dhillon, Simrat

AU - Witteveldt, Jeroen

AU - Gatherer, Derek

AU - Owsianka, Ania M.

AU - Zeisel, Mirjam B.

AU - Zahid, Muhammad N.

AU - Rychłowska, Małgorzata

AU - Foung, Steven K. H.

AU - Baumert, Thomas F.

AU - Angus, Allan G. N.

AU - Patel, Arvind H.

PY - 2010/6

Y1 - 2010/6

N2 - Cell culture-adaptive mutations within the hepatitis C virus (HCV) E2 glycoprotein have been widely reported. We identify here a single mutation (N415D) in E2 that arose during long-term passaging of HCV strain JFH1-infected cells. This mutation was located within E2 residues 412 to 423, a highly conserved region that is recognized by several broadly neutralizing antibodies, including the mouse monoclonal antibody (MAb) AP33. Introduction of N415D into the wild-type (WT) JFH1 genome increased the affinity of E2 to the CD81 receptor and made the virus less sensitive to neutralization by an antiserum to another essential entry factor, SR-BI. Unlike JFH1WT, the JFH1N415D was not neutralized by AP33. In contrast, it was highly sensitive to neutralization by patient-derived antibodies, suggesting an increased availability of other neutralizing epitopes on the virus particle. We included in this analysis viruses carrying four other single mutations located within this conserved E2 region: T416A, N417S, and I422L were cell culture-adaptive mutations reported previously, while G418D was generated here by growing JFH1WT under MAb AP33 selective pressure. MAb AP33 neutralized JFH1T416A and JFH1I422L more efficiently than the WT virus, while neutralization of JFH1N417S and JFH1G418D was abrogated. The properties of all of these viruses in terms of receptor reactivity and neutralization by human antibodies were similar to JFH1N415D, highlighting the importance of the E2 412-423 region in virus entry.

AB - Cell culture-adaptive mutations within the hepatitis C virus (HCV) E2 glycoprotein have been widely reported. We identify here a single mutation (N415D) in E2 that arose during long-term passaging of HCV strain JFH1-infected cells. This mutation was located within E2 residues 412 to 423, a highly conserved region that is recognized by several broadly neutralizing antibodies, including the mouse monoclonal antibody (MAb) AP33. Introduction of N415D into the wild-type (WT) JFH1 genome increased the affinity of E2 to the CD81 receptor and made the virus less sensitive to neutralization by an antiserum to another essential entry factor, SR-BI. Unlike JFH1WT, the JFH1N415D was not neutralized by AP33. In contrast, it was highly sensitive to neutralization by patient-derived antibodies, suggesting an increased availability of other neutralizing epitopes on the virus particle. We included in this analysis viruses carrying four other single mutations located within this conserved E2 region: T416A, N417S, and I422L were cell culture-adaptive mutations reported previously, while G418D was generated here by growing JFH1WT under MAb AP33 selective pressure. MAb AP33 neutralized JFH1T416A and JFH1I422L more efficiently than the WT virus, while neutralization of JFH1N417S and JFH1G418D was abrogated. The properties of all of these viruses in terms of receptor reactivity and neutralization by human antibodies were similar to JFH1N415D, highlighting the importance of the E2 412-423 region in virus entry.

UR - http://www.scopus.com/inward/record.url?scp=77951984160&partnerID=8YFLogxK

U2 - 10.1128/JVI.02153-09

DO - 10.1128/JVI.02153-09

M3 - Journal article

AN - SCOPUS:77951984160

VL - 84

SP - 5494

EP - 5507

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 11

ER -