Figure 7.
Co-evolution Mechanisms of the PC64 Virus and Immune System and Lessons for Immunogen Design
The founder PC64 virus has a strong electropositive charge at the Env three-fold axis. (1) PCT64 antibody precursor with anionic CDRH3 targets the apex and initiates (2) the lineage maturation. Interplay between the virus and immune response results in a gradual decrease of the positive charge of the V2 apex plus changes in the glycan composition of Env and (3) the antibody evolving a steeper angle of approach, rigid CDRH3 allowing deeper penetration into the three-fold axis, and modulation of the charge of the surface contacting the glycan canopy. These changes lead to high potency against autologous virus but no breadth against heterologous viruses. (4) Further maturation leads to modest breadth and potency. At later stages of infection, these changes limit the antibody lineage evolution while the apex charge becomes neutral, leading to virus escape. PC64 embodies several of the properties of the (5) broad and potent PGT145 bnAb lineage but does differentiate down a path that prevents further productive maturation. A potential path of PC64 response may be diverted toward PGT145-like response by altering V1 and V2 loop lengths and by adding or removing apex glycans.