Technology firm XtalPi utilised artificial intelligence models to nominate a preclinical candidate targeting the MPER region of HIV-1 gp41 for portfolio company Viva-Thera within seven months.

Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (

HIV-1 infection begins with Env-gp120 binding to the CD4 receptor and CD4-triggered Env conformational changes that enable viral entry. To identify key Env s...

The HIV-1 envelope glycoprotein complex (Env) is a trimeric, heavily glycosylated class I viral fusion protein that protrudes from the viral membrane and serves as the sole mediator of viral entry into host cells9. Each Env protomer consists of a surface gp120 glycoprotein non-covalently associated with a transmembrane gp41 glycoprotein, together forming a metastable trimer that is primed to undergo receptor-induced conformational rearrangements during viral entry10. High-resolution structural studies have shown that gp120 comprises a conserved inner domain, a heavily glycosylated outer domain, variable loops (V1–V5), and a bridging sheet that forms a critical component of the co-receptor binding interface following receptor engagement11. In contrast, gp41 contains the N-terminal fusion peptide, heptad repeat regions (HR1 and HR2), membrane-proximal external region (MPER), transmembrane domain, and cytoplasmic tail (CT). These domains collectively mediate membrane fusion, with the fusion peptide and HR1/HR2 driving six-helix bundle formation, the MPER contributing to membrane destabilization and serving as a conserved target for broadly neutralizing antibodies, and the CT coordinating Env incorporation during virion assembly10. The extensive N-linked glycosylation of gp120 forms a dense glycan shield that masks conserved protein epitopes from antibody recognition. Each HIV-1 Env trimer carries approximately 90 N-linked glycans (≈30 per gp120 protomer),...

Background: Killed Whole Cell Genome-Reduced Bacteria (KWC/GRB), a versatile vaccine platform, can produce very low cost, thermostable, easily manufactured vaccines expressing complex immunogens that include potent immunomodulators. This system supports iterative optimization through a Design–Build–Test–Learn (DBTL) workflow aimed at enhancing immunogenicity. We applied this approach to developing HIV-1 gp41 Membrane-Proximal External Region (MPER) vaccines using the scaffolded MPER antigen, 3AGJ, a recombinant heterologous protein engineered to mimic MPER structures recognized by broadly neutralizing monoclonal antibodies (bNAbs). Methods: Five KWC/GRB vaccines expressing versions of 3AGJ were designed, including versions linked to immunomodulators and multimers of the immunogen. Display on the surface of the bacteria was evaluated by flow cytometry using the broadly neutralizing monoclonal antibody 2F5. Outbred HET3 mice were vaccinated intramuscularly, and MPER-spe

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic fe...

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and ... View article...

For the first time, an allosteric interaction (that is, a regulation mechanism whereby enzymes can be activated or de-activated) between a protein, which forms part of the sheath of the Human Immunodeficiency Virus (HIV) and the antibody 2F5 (FAB), a potent virus neutralizer has been discovered. This important scientific breakthrough could help specialists to understand the mechanisms behind generating immune responses and help towards the design of future vaccines against the HIV  virus.

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High mutation and replication rates of HIV-1 result in the continuous generation of variants, allowing it to adapt to changing host environments. Mutations often have deleterious effects, but varia...

HIV-1 broadly neutralizing antibodies (bNAbs) sharing genetic features and binding modes that arise in multiple individuals present attractive templates for vaccine design. Cale et al. describe a highly glycan-dependent HIV-1 bNAb that prefers high-mannose glycoforms and targets the HIV-1 gp120-gp41 interface, similar to bNAb 35O22, thereby defining a multidonor class.

For engineering of light-controlled protein splicing (Fig. 1), we tested several sites to insert the double VVD (LightR) allosteric switch51 into gp41-1. We selected insertion sites targeting the loops connecting beta sheets in the available crystal structure53. We also tested...