In addition to Vpu and Nef action, structural features of HIV-1 Env also influence the sensitivity of HIV-1 to ADCC. The Phe43 cavity, located at the interface of the inner and outer domains of gp120, allows the engagement with CD4 via its Phe43 residue [
12] and modulates the propensity of Env that sample the CD4-bound conformation [
13]. Substitution of the well-conserved group M serine at position 375 by a larger residue such as tryptophan or histidine was found to fill the Phe43 cavity and result in the spontaneous sampling of a conformation closer to the CD4-bound state [
13]. Accordingly, we showed that filling this cavity with a histidine or tryptophan residue increased the susceptibility of HIV-1-infected cells to ADCC [
14] (Fig.
1c). Surprisingly, while residue S375 is well-conserved among group M HIV-1 isolates, the predominant CRF01_AE strain in Thailand where the RV144 trial took place has a naturally-occurring histidine at this position (H375). Interestingly, H375 was recently shown to be important for CD4 binding in this strain [
15] and its substitution by a serine (H375S) substantially reduces ADCC against CRF01_AE-infected cells mediated by Abs isolated from RV144 vaccinees [
14]. While a functional coevolution between the Phe43 cavity and the gp120 inner domain layers appears to compensate for the presence of H375 in CRF01_AE Envs [
15], our results raise the intriguing possibility that this unique H375 polymorphism present in the circulating strains in Thailand might have contributed to the efficacy of the RV144 trial by naturally exposing CD4i ADCC-mediating epitopes. Although our results suggest that H375 might represent a point of vulnerability for the virus in vaccine settings, they do not necessarily imply that viral strains carrying the H375 polymorphism would be better controlled once the infection has been established. Supporting this, a recent study showed that filing the Phe43 cavity by residue 375 substitutions in simian-human immunodeficiency viruses (SHIV) enhanced viral replication in rhesus macaques [
16].