HIV 1 and SARS CoV 2 immunogen design

Abstract

Human Immunodeficiency Virus (HIV-1) is the aetiologic agent of AIDS. Presently there are ~38 million HIV-1 infected individuals worldwide and ~1 million deaths in 2019. Since its discovery, the quest for vaccine candidate for HIV-1 is alive, yet no effective vaccine exists till date. HIV-1 viral displayed Envelope (Env) protein is the primary viral target of the humoral immune system and is thus an obvious vaccine candidate. The historic RV144 HIV-1 clinical trial resulted in a modest efficacy of the gp120 clade B/E vaccine candidate and renewed hope in finding a HIV-1 vaccine. However, monomeric gp120 does not induce protective antibodies and native-like trimeric Env was hypothesized to be a better candidate to induce broadly neutralizing antibodies. The recent structure of the BG505SOSIP.664 gp140 ectodomain reinvigorated interest in rational immunogen design. Chapter 1 outlines the HIV-1 virus, organisation, and structures of the Env ectodomain gp140, gp120, gp41 and various strategies to elicit neutralizing antibodies. Chapter 2 provides proof of principle of a method involving a computational sequence and structure guided Rosetta mutational scanning approach PROSS, to generate high yielding variants of the Env derivative gp140 without altering the trimeric structure and antigenicity. Chapter 3 utilizes the approach of cyclic permutation to rationally design trimeric gp120 derivatives that display a native V1V2 apex and retain binding to quaternary epitope directed bNAbs such as PGT145 and PGDM1400. Further, a nanoparticle display of the cyclic permutant was carried out to improve the immunogenicity of these potentially attractive vaccine candidates. Chapter 4 utilizes a structure guided approach to derive stable Env ectodomain variants by a cyclic permutation design strategy and describes an approach to engineer disulfides at the trimer Apex to covalently link the trimers for obtaining dynamically stable Env variants. HIV-1 Env displays conserved epitopes that are targeted by broadly neutralizing antibodies