Stabilization of HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

HIV-1 has evolved various tricks to prevent the development of a potent humoral immune response. The only target for neutralizing antibodies (NAbs) is the HIV-1 envelope glycoprotein (Env), which is the sole viral protein embedded in the viral membrane. It consists of three gp41 subunits and three gp120 subunits, forming a trimeric complex of heterodimers. Env displays several characteristics that hamper the production of effective neutralizing antibodies. The Env trimer is masked by flexible variable domains and a dense glycan shield, preventing the development of antibodies against more conserved underlying protein domains. Furthermore, the Env trimer is conformationally flexible, fluctuating between closed and more open conformations. The conformational flexibility of the functional Env trimer, as well as the expression of non-functional Env products on the viral membrane, drive the induction of off-target non-neutralizing antibodies (non-NAbs), that do not recognize the functional Env trimer. Despite the evasion mechanisms displayed by HIV-1 to prevent the emergence of NAbs, broadly neutralizing antibodies (bNAbs) develop in 10-30% of HIV-1 infected individuals, typically between 1 to 3 years after infection. Although the patients do not benefit from these bNAb response, studying the characteristics of these bNAbs is of significant value for the design of HIV-1 vaccines aimed at inducing similar responses.
This thesis describes the design of stabilized recombinant HIV-1 Env trimer immunogens that closely mimic the native envelope spike, with the aim of providing a platform for the induction of bNAbs. We devised various stabilization strategies to improve the presentation of bNAb epitopes on HIV-1 Env trimers, while reducing the presentation of non-Nab epitopes. To do so, we introduced modifications that improved the overall stability of Env trimers and/or the stability of specific subdomains.