A Summary of ProSci’s Research on HIV – ProSci

ProSci’s roots lie in the research of the Human Immunodeficiency Virus and working to develop a neutralising vaccine against it. Below is an “abstract of abstracts” summarising the research performed over the last several years that has built their business from the ground up.

ProSci’s HIV Research Summary

The Human Immunodeficiency Virus type 1 (HIV-1) is the causative agent for Acquired Immunodeficiency Syndrome (AIDS). The HIV envelope glycoprotein (Env) spike is the sole target of broadly neutralising antibodies (bnAbs). HIV Env is one of the most heavily glycosylated proteins known with 50% of its mass consisting of host-derived glycans. Glycans are viewed as self-molecules by the host immune system and hence are non-immunogenic. It is believed that the virus has evolved to incorporate a large number of N-glycosylation sites to protect the backbone from antibody-mediated neutralization. In the past several years, a large number of HIV bnAbs have been isolated and characterised from elite (10-30% HIV positive) patients who have been infected with HIV for 2-3 years. Most of those bnAbs (e.g. b12, VRC01, VRC01, 4E10, 10E8) target the protein backbone, however, the new emerging antibodies (e.g. PG9, PGT121, PGT145, PGT128) also interact with glycans at specific locations on the Env protein. Research at ProSci has been focused on targeting the “glycan” using a modified strain of Saccharomyces cerevisiae (brewer’s yeast) for the development of the HIV vaccine. We generated triple mutant (TM) yeast strain, which has a deletion of 3 genes (Och1, Mnn1 and Mnn4) involved in the N-glycosylation pathway that results in the expression of Man8 glycans on the surface of its glycoproteins.[1] Few glycoproteins expressed and purified in the TM yeast strain can cross-react with the glycan targeting bnAb 2G12. This suggests that the glycans resemble those on HIV-1, and can be developed as a vaccine to generate 2G12-like antibodies, which are able to target high-mannose glycans.[2] Immunisation studies in rabbits with TM yeast expressed glycoproteins as antigens elicited antibodies that are able to bind to various gp120s and gp140 trimers from different clade viruses.[3] However, the sera cannot neutralise the pseudovirus. This implies that the underlying structure of the glycoprotein is important for elicitation of antibodies against the native trimeric Env protein.[4] The current strategy involves training the immune system such that it evolves to elicit anti-glycan antibodies that are able to recognise native trimeric Env protein and neutralise HIV-1 pseudoviruses.[5]

HIV research at ProSci is continuing forward while focusing its efforts on eliciting the proper immune response for generating antibodies against HIV glycans.

Originally posted by ProSci: www.prosci-inc.com/blog/ProSci-Research-Summary/

References

1. Luallen RJ, Lin J, Fu H, Cai KK, Agrawal C, Mboudjeka I, Lee F-H, Montefiori D, Smith DF, Doms RW, Geng Y. An engineered Saccharomyces cerevisiae strain binds the broadly neutralizing human immunodeficiency virus type 1 antibody 2G12 and elicits mannose-specific gp120-binding antibodies.; J Virol; 2008 Jul;82(13):6447-57. doi: 10.1128/JVI.00412-08.
2. Luallen RJ, Fu H, Agrawal-Gamse C,  Mboudjeka I, Huang W, Lee F-H, Wang L-X, Doms RW, Geng Y. A yeast glycoprotein shows high-affinity binding to the broadly neutralizing human immunodeficiency virus antibody 2G12 and inhibits gp120 interactions with 2G12 and DC-SIGN; J Virol; 2009 May;83(10):4861-70. doi: 10.1128/JVI.02537-08. Epub 2009 Mar 4.
3. Luallen RJ, Agrawal-Gamse C, Fu H, Smith DF, Doms RW, Geng Y. Antibodies against Manalpha1,2-Manalpha1,2-Man oligosaccharide structures recognize envelope glycoproteins from HIV-1 and SIV strains. Glycobiology; 2010 Mar;20(3):280-6. doi: 10.1093/glycob/cwp184. Epub 2009 Nov 17.
4. Agrawal-Gamse C, Luallen RJ, Liu B, Fu H, Lee F-H, Geng Y, Doms RW. Yeast-elicited cross-reactive antibodies to HIV Env glycans efficiently neutralize virions expressing exclusively high-mannose N-linked glycans. J Virol. 2011 Jan;85(1):470-80. doi: 10.1128/JVI.01349-10. Epub 2010 Oct 20.
5. Zhang H , Fu H, Luallen RJ, Liu B, Lee F-H , Doms RW , Geng Y. Antibodies elicited by yeast glycoproteins recognize HIV-1 virions and potently neutralize virions with high mannose N-glycans. Vaccine. 2015 Sep 22;33(39):5140-7. doi: 10.1016/j.vaccine.2015.08.012. Epub 2015 Aug 13.