Patrice DEBRE is professor of immunology at University Pierre et Marie Curie and Pitié-Salpêtrière hospital. He directed a federative institute on infection and immunity, an INSERM laboratory and a department of immunology. Pr Patrice Debre has been an ambassador for the fight against HIV and communicable diseases and French representative at the Global Fund, UNITAID, EDCTP, UNAIDS, RBM. Well know specialist of HIV, he is author of more than 350 articles in Immunology, Immunopathology and Immunogenic. He is a corresponding member of the French Academy of Medicine.
Objective: The hallmark of most successful vaccine is the ability to induce cross-reactive neutralizing antibodies (NAbs). Over the ensuing years, we have shown that a highly specific and conserved motif of the gp41, called 3S, induces expression of NKp44L, the cellular ligand for an acitivating NK receptor on CD4+ T cells render them more sensitive to autologous NK lysis. The aim of this study was to show that a specific substitution inside this 3S motif permits the development of NAbs while preserving the capacity to block CD4 depletion (Petitdemange et al Clin Inf Dis 2013). Methodology: To further charaterized the 3S peptide, an alanine-scanning inside the 3S motif was performed. We tested such effect on (a) the capicities to infect cells and (b) the ability of the corresponding peptides to induce production of Ab that elicits viral neutralisation and/or inhibits NKp44L expression on CD4 T cells and NK cell function. Generation of monoclonal NAbs, and characterization of their Vh et Vκ domains. Results: In this study, an alanine-scanning allowed us to identify a specific position in the 3S motif that totally inhibits HIV entry and expose it to a broad spectrum of neutralizing antibodies. Importantly, for the first time, we show that that a specific amino-acid substitution within a highly linear motif of the gp41 elicit strong neutralization capacity with impressive magnitude, breadth and ability to durability over cross clade viruses. Furthermore, our data also show that this acquisition of neutralization capacities preserves the unique ability of anti-3S Ab to inhibit NKp44L expression on CD4+ T cells and their sensitivity to NK lysis. The generation of monoclonal NAbs has also permit their molecular identification Conclusion: Our finding suggest that a specific substitution into the 3S motif may lead to the generation of bNAbs directed against the highly conserved motif of the gp41 and will provide foundation for novel vaccine strategies based on specific substitutions in highly conserved motif of the HIV Env protein.