Some people, known as Highly Exposed SeroNegative (HESN), do not contract HIV despite having unprotected sex with HIV-positive partners. Their immune system represents a unique model for understanding the natural mechanisms of protection against HIV infection.
The researchers focused their analysis on the specific antibodies present in mucous membranes, IgA, which form a first line of defense and play a key role in this protection. In HESNs, these IgA antibodies target a specific region of the viral protein gp41, preventing the virus from fusing with cells and thus blocking infection. In other words, they close the "entry point" that the virus uses.
Based on this discovery, the researchers characterized the epitope of one of these IgA antibodies, which includes a small segment of each of the two helices that form gp41, giving this epitope "two arms." This epitope was synthesized as a 12-amino-acid peptide, named P7. Unexpectedly, the researchers showed that P7 replicated the action of these protective antibodies. P7 binds to gp41 and prevents the virus from making the structural changes necessary for fusion with the cell membrane. Its unique "two-arm" configuration allows it to simultaneously target two parts of gp41, blocking fusion with the cell, a key step in viral entry. Indeed, the P7 peptide acts as an inhibitor, mimicking the natural mucosal protection observed in HESNs (human neonatal serotonin syndromes). In contrast, the broad-spectrum neutralizing anti-HIV IgG antibodies, on which HIV vaccine research is focused, circulate in the blood.
P7 is active against several HIV strains, including the so-called "founder" strains (those responsible for initial infections), demonstrating its broad spectrum of efficacy. In addition to its direct antiviral action, P7 could also serve as an immunogen in new vaccination strategies by reproducing the natural protection observed in HESNs, according to the principle of reverse vaccinology.
By combining antiviral and immunogenic properties, P7 represents a promising avenue for the development of innovative treatments and vaccines against HIV, opening new perspectives in the fight against this infection.
Figure legend: In individuals exposed to HIV but remaining seronegative, and therefore protected from infection, mucosal IgAs contribute to protection against HIV by specifically binding to the viral envelope and thus preventing infection. The P7 peptide is the conformational epitope recognized by one of these mucosal IgAs, identified through screening of a random peptide library and then by in silico modeling. This P7 peptide binds to the HIV envelope and blocks viral fusion with the target cell in vitro, thereby preventing HIV infection of target cells. Lipidation of the peptide (Lipo-P7) enhances its antiviral activity. Furthermore, this lipidation may serve as an adjuvant in a vaccination strategy. This Lipo-P7 vaccine candidate is currently being evaluated for its ability to induce protective IgA antibodies against HIV in vivo.
Reference
Sahnoune I, Cottignies-Calamarte A, Dauvilliers A, Essemiah K, Bouceba T, Piesse C, Tudor D, Bomsel M. The conformational epitope of a gp41-specific mucosal protective IgA binds to the HIV-1 envelope and neutralizes infection. Acta Pharmacol Sin. 2025 Nov;46(11):3009-3021. doi: 10.1038/s41401-025-01535-5. Epub 2025 Jun 5. PMID: 40473821; PMCID: PMC12552590.
