The potential caveolin-1 binding domain (CBD), referred to as CBD1 and CBD2, is highly conserved in the transmembrane envelope glycoprotein of various HIV-1 and HIV-2 isolates, respectively. However, HIV-1 neutralizing antibodies raised against the synthetic CBD1 peptide (SLEQIWNNMTWMQWDK) do not cross-react with the CBD2 peptide (SLTPDWNNMTWQEWER) and have no effect on HIV-2 infection. Here we show that the CBD2 peptide is not immunogenic under similar immunization conditions as the CBD1 peptide. Moreover, the CBD1 but not the CBD2 peptide has the capacity to bind caveolin-1 in crude cell extracts thus suggesting the existence of structural and/or conformational differences between CBD1 and CBD2. Accordingly, circular dichroism spectroscopy and fluorimetry analysis indicated that CBD1 but not CBD2 could adopt a defined secondary structure and form a complex with a peptide corresponding to the caveolin-1 scaffolding domain, which is the site of interaction of caveolin-1 with various proteins. In line with these observations, CBD1 but not CBD2 binds cells and forms large aggregates at the plasma membrane by colocalizing with cytofacial caveolin-1. This latter is dependent on the lipid raft integrity of the plasma membrane. Supporting that the ability to penetrate into plasma membranes is sustained by folding at the interface, CBD1 but not CBD2 has the capacity to insert into lipid monolayers, penetrate into artificial membranes and adopt a beta-sheet conformation in presence of lipid vesicles. These structural determinants and membrane partitioning properties could account for the immunogenicity of the CBD1 peptide in various animals.