The V3 loop of the human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein (Env) becomes exposed after CD4 binding and contacts the coreceptor to mediate viral entry. Prior to CD4 engagement, a hydrophobic patch located at the tip of the V3 loop stabilizes the non-covalent association of gp120 with the Env trimer of HIV-1 subtype B strains. Here, we show that this conserved hydrophobic patch (amino acid residues 307, 309 and 317) contributes to gp120-trimer association in HIV-1 subtype C, HIV-2 and SIV. Changes that reduced the hydrophobicity of these V3 residues resulted in increased gp120 shedding and decreased Env-mediated cell-cell fusion and virus entry in the different primate immunodeficiency viruses tested. Thus, the hydrophobic patch is an evolutionarily conserved element in the tip of the gp120 V3 loop that plays an essential role in maintaining the stability of the pre-triggered Env trimer in diverse primate immunodeficiency viruses.
The twin-cysteine motif (TCM) in the V2 loop region of gp120, identified in our previous report on the simian immunodeficiency virus mac239 (SIVmac239), is a conserved evolutionary element in all primate lentiviruses except for HIV-1 which has lost the TCM during cross-species transmission. In this study, we have further explored the TCM in other SIV and HIV-2 strains. Our data shows that strains from different evolutionary lineages have different phenotypes when the twin-cysteines are removed. In the SIVsm/HIV-2 lineage, removal of the twin-cysteines decreases envelope trimer stability, but in the SIVagm lineage, a blockage of gp160 processing is observed. Molecular modeling has confirmed that the twin-cysteines do form a disulfide bond in the gp120 subunit, which interacts with the V1 loop to stabilize the envelope trimer. Therefore, we hypothesize that if the TCM is added back to HIV-1, it will enhance envelope stability for vaccine immunogen design.
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