Viral escape mutations in RV217 participants during the acute stage of HIV infection.
(A) Mutations observed in the RV217 participants – 7, 61, 94, and 100 are placed on HIV-1 BG505 pre-fusion trimer structure (PDB ID: 4TVP). Surface model showing dominant mutations (blue) falling on the solvent-exposed regions of the Env (gray) but not on the non-exposed or buried region (red). Modeling was done with PyMol (ver. 1.74) molecular visualization software and surface-exposed residues were defined as all residues that had >5Å2 exposure to the solvent. (B) Mutational hotspots in the env sequence based on the genetic diversification of T/F viruses from all four participants. Total number of mutations in a particular region is plotted on the y-axis against residue positions on the env sequence (x-axis), with reference to HXB2 strain. The Env regions (labeled on top) with gray background showed high frequency of mutations. (C) Phylogenetic tree displaying T/F07 virus evolution in participant_7. The evolutionary tree was constructed by the neighbor-joining method, rooted to the T/F07 virus sequence. The viruses are designated corresponding to the time post-infection; 1 wk, 1 month (4-wks)) or 6-month (24 wks) at the nodes of the branches. Prominent diverging mutations are labeled on the respective branches of the tree in red (V1V2 region) and gray (another region). (D) Dominant mutations that occurred until 24-wk post-infection in participant_7 are modeled on a ribbon model of the T/F07 trimer, generated through homology modeling using BG505 trimer (PDB ID: 4TVP) as a template. The zoomed-in image of V1V2 domain is shown to highlight the positions of V2-specific mutations, H173Y (red) and 3-residue deletion, DSV (blue). Deletion in the variable, V4 region is depicted in bright green and mutation in the conserved C2 region, K236T substitution, is shown in magenta. (E) A color-coded 4-5 β-stranded (A-D) conserved Greek-key motif structure of V1V2 domain is represented showing residue 173 on the C β-strand. (F) Snapshot of V1V2 sequences of T/F viruses from each RV217 participant under study. Major structural features of V1V2 region; semi-conserved four β-strands (A, B, C and D) and hypervariable V1 and V2 loops are labeled on top of the sequence. Prominent V1V2-specific mutation sites (observed in >50% of circulating viruses) until 24-wks are highlighted in red in the respective T/F virus sequence isolated from participants – 7, 61, 94 and 100.