The Association of the Gp120 V3 Loop with Envelope Trimmer Stabilization in HIV-1 Subtype C Viruses
Despite recent advances, HIV-1 is still a major global pathogen that affects over 34 million individuals worldwide, with the vast majority of infections occurring in sub-Saharan Africa. As we know the HIV-1 subtype C is the major subtype that is responsible for infections in Africa, indicating that an effective vaccine against this subtype is crucial. Our focus is on HIV-1 envelope glycoprotein stabilization in an effort to design an immunogen based vaccine. In a previous report, we discovered a hydrophobic patch region of the V3-loop in HIV-1 subytpe B that is contributing to envelope glycoprotein trimer stability. Interestingly, this hydrophobic patch appears to be well conserved in sequences and locations across HIV-1 subtype strains and even HIV-2 and SIV. In this report, we have demonstrated that the V3-loop hydrophobic patch is preserved and also functional in HIV-1 subtype C strains. Taking a mutational approach, we confirmed in a panel of subtype C viruses that this hydrophobic patch contributes to envelope glycoprotein trimer stability, as alterations of these residues to non-hydophobic residues resulted in a significant increase in envelope protein shedding, which correlates to a decrease in membrance fusion and in infectivity. Characterizing the role of the V3-loop hydrophobic patch in the structural stability of this envelope trimer will help us to stabilize the envelope trimeric complex for the development of the trimer-based HIV-1 vaccine.