Poster Presentation Lorne Infection and Immunity 2018

A novel glycan deletion mutation in HIV-1 Envelope protein enhances exposure of key broad neutralisation epitopes, including in a Transmitted/Founder Env (#133)

Hannah A. D. King 1 2 , David N. Harrison 1 , Vani S. Narasimhulu 1 , Christine Langer 1 , Rob J. Center 1 2 , Heidi E. Drummer 1 2 3 , Andy Poumbourios 1 3
  1. Centre for Biomedical Research, Burnet Institute, Melbourne
  2. Department of Microbiology and Immunology, Peter Doherty Institute, University of Melbourne, Melbourne
  3. Department of Microbiology, Monash University, Clayton

An effective prophylactic vaccine for HIV will likely require the elicitation of neutralising antibodies directed towards the Envelope protein (Env) of HIV. In particular, broadly neutralising antibodies (bNAbs) capable of mediating neutralisation against a wide variety of HIV strains would be desirable. A major obstacle to the elicitation of bNAbs is an immune evasion strategy whereby conserved neutralisation epitopes are rendered subdominant due to shielding by glycans or due to competition with higher affinity non-neutralising epitopes for B cell receptors. Our aim is to enhance the exposure and potentially the immunogenicity of bNAb epitopes in Env vaccines via the introduction of a novel mutation, ΔN, with the intention of redirecting the immune response to bNAb epitopes. The introduction of the ΔN mutation into soluble protein constructs of the AD8 strain of Env enhanced the exposure of the epitopes for multiple bNAb specificities. A preliminary immunogenicity study in guinea pigs revealed that AD8 ΔN elicited significantly higher titres of antibodies able to block the binding of bNAbs whose epitope exposure was enhanced in this protein. This enhancement of bNAb epitope exposure has also been observed when the ΔN mutation is introduced into other Env strains. One Env strain in which a large ΔN-mediated epitope enhancement is observed is SC45, a Transmitted/Founder (T/F) strain of Env. As T/F Env best resemble circulating Env strains, vaccination with a T/F Env is a promising strategy for the elicitation of protective immune responses. Additionally, SC45 Env displays highly favourable biophysical characteristics, necessary for production as a vaccine, and immunogenicity studies using this Env are currently underway.