Early studies have suggested that high serum neutralizing titers were typically required for protection against high-dose SHIV mucosal challenge. More recently, it has been reported that lower serum neutralizing antibody titers were also protecting against repeated low-dose mucosal SHIV challenge. Human evidence supporting mucosal antibodies as protective mechanism came from HIV-1 highly exposed persistently seronegative subjects. IgAs purified from HEPS were able to neutralize infection of peripheral blood mononuclear cells by HIV-1 isolates and to inhibit HIV1 transcytosis across mucosal epithelium in vitro. These inhibitory mucosal antibodies were shown to be specific to gp41 and the QARILAV motif present on the N-helix was one of the targeted epitopes. A recent study on HEPS women in an HIV-1 serodiscordant relationship has suggested that exposure to an HIV-infected partner with low plasma viral load favors the induction of cervicovaginal IgAs with 3,4,5-Trimethoxyphenylacetic acid antiviral activity, which may contribute to reduce HIV-1 acquisition. The membrane proximal external region of gp41 is also targeted by the broadly neutralizing IgG monoclonal antibodies 2F5 and 4E10 and more recently by the 10E8 that binds the conserved residues Trp680 and Lys/Arg683. Although complete in vivo protection and sterilizing immunity in NHP were only recently reported for 2F5 and 4E10, these MPER specific antibodies were already known for their Albaspidin-AA ability to block HIV transcytosis and cell infection in vitro, as also observed with mucosal IgAs from HEPS individuals. All these observations suggest that gp41 might be an attractive antigen to be included in prophylactic HIV-1 vaccines. Gp41 is more conserved than gp120 and mediates the fusion process with the target cell membrane. It also contains the conserved mucosal receptor binding motif used by HIV-1 for binding to the galactosyl-ceramide present on epithelial and dendritic cells, which corresponds to the P1 peptide originally defined by the gp41 sequence 650�C685. In a previous study, the P1 and a truncated trimeric recombinant gp41 protein were modified for allowing lipidation and surface anchorage on virosome, also called immunopotentiating reconstituted influenza virosome. Virosome has a dual function : i) Lipid carrier for antigen delivery, mimicking the native viral membrane environment, which may be important for gp41 antigens; and ii) A safe human adjuvant. In contrast to what was observed with many viral vectors, pre-existing antibodies against the influenza hemagglutinin on virosomes may help to deliver the antigens/virosomes to antigen presenting cells and they are not preventing vaccination with virosomes. The HIV-1 candidate vaccine constituted of virosome-P1 and virosome-rgp41 led to the “Proof of Concept” that vaccineinduced mucosal antibodies protect NHP against vaginal heterologous virus challenges. All animals immunized by the combined intramuscular and intranasal routes were fully protected, as compared to 50% protection for the animal group that received only intramuscular vaccinations. Protection was correlated with the presence of gp41-specific vaginal secretions exhibiting transcytosis inhibition and antibodydependent cell-mediated cytotoxicity, while serums had no detectable antiviral activities in vitro. These results have clearly challenged the paradigm that mucosal protection against sexually transmitted HIV-1.