IXI triplet residues within the Env-V3 tip can influence the replication potential of R5-tropic HIV-1

抄録

The HIV-1 envelope glycoprotein (Env)-gp120 plays a critical role in viral entry by binding to the receptor CD4 and coreceptors CCR5/CXCR4. The V3 loop in CCR5-tropic HIV-1 Env-gp120 is a key domain responsible for interacting with CCR5. Based on virus mutation and adaptation studies, our structural modeling predicted that the IXI triplet residues within the V3 loop of Env-gp120 interact with hydrophobic cores in CCR5, potentially modulating viral infectivity. In this study, we investigated the functional significance of the IXI triplet in HIV-1 replication. Substitutions at the central “X” position of the IXI triplet significantly affected viral replication in both macaque and human cell lines without altering Env expression. Combinatorial mutations with the V3 tip residue G310R showed either enhancing or suppressive effects on replication in macaque cells, highlighting a complex interplay between the IXI triplet and V3 tip. Furthermore, the impact of these mutations varied between different HIV-1 strains, suggesting that some strain-specific sequence/structural context(s) is critical for the observed biological effect. Taken together, these findings indicate that the IXI triplet can be a novel motif influencing HIV-1 replication and underscore the importance of V3 loop variability in coreceptor interaction and viral growth potential. J. Med. Invest. 73 : 80-87, February, 2026