Science Bite (3 minute oral presentation with PPT in live session with pre-recorded e-poster) Lorne Infection and Immunity 2021

Characterization of a monoclonal antibody towards the N-terminal hypervariable region 1 (HVR1) and epitope I of Hepatitis C Virus Glycoprotein E2 (#102)

Felicia Schlotthauer 1 2 , Chan-Sien Lay 3 , Irene Boo 1 , Yousef Alhammad 1 , Jun Gu 1 4 , Rob Center 1 , Pantelis Poumbourious 1 , Fasseli Coulibaly 3 , Heidi Drummer 1 2 4
  1. Viral Entry and Vaccines Laboratory, Life Science, Burnet Institute, Melbourne, VICTORIA, Australia
  2. Department of Microbiology and Immunology at the Peter Doherty Institute, The University of Melbourne, Melbourne, Victoria, Australia
  3. Infection and Immunity Program, Monash Biomedicine Discovery Insitute, Monash University, Clayton, VIC, Australia
  4. Department of Microbiology, Faculty of Medicine, Nursing and Health Sciences,, Monash University, Melbourne, Victoria, Australia

A Hepatitis C virus vaccine is urgently needed to achieve global elimination. Hepatitis C is one of the most antigenically variable human pathogens and an effective vaccine must generate immunity in the majority of the human population.
Glycoprotein E2 is present on the virion surface and is a major target of neutralizing antibodies which can prevent infection. All neutralizing domains identified to date work by blocking interaction between E2 and cell surface receptor CD81. The N-terminal hypervariable region 1, HVR1 (384-408) is an immunodominant region within E2 and elicits neutralizing antibodies that are usually type specific. HVR1 is known to play an essential role in binding of infectious serum derived HCV particles to scavenger receptor class B type 1 and glycosaminoglycans on the cell surface, essential for HCV entry. Cross neutralizing antibodies that include amino acids within HVR1 have not been characterized.
We have identified a novel rodent monoclonal antibody, MAb33, that binds to an unusual epitope bridging HVR1 and the adjacent target of broadly neutralizing antibodies referred to as epitope I (408-423). MAb33 potently neutralizes genotype 1a viruses, and also has the ability to cross-neutralize 3 different HCV genotypes, however, it only weakly blocks the interaction between E2 andCD81 suggesting its mechanism of neutralization is distinct from previously defined bNAbs.
We have defined the epitope of MAb33 and for the first time resolved its structure in complex with its epitope at 2Å resolution. The structure of the epitope is a helix and is in a different conformation to what is observed in unliganded structures that include this region of E2. The results suggest that this region could be flexible, raising the question whether there is a preferred conformation detected by neutralizing antibodies.
Studies using MAb33 and full length E2 will provide novel insight into the structure of HCV E2 and properties of antibodies directed towards HVR1. We will further perform a sero-survey to establish whether MAb33-like antibodies occur in infected individuals, which will help inform antigen development for HCV vaccines.