A Computational HIV-1 Sequential Immunization Series Targeting the VRC01 Germline Pathway

Abstract

A five-dose sequential immunogen series designed to guide germline VRC01-class B cells toward the HIV-1 gp120 CD4-binding site. Designed and validated using AlphaFold, ProteinMPNN, and PDB structures 3NGB/5IES/5IDL. The series achieves pTM scores of 0.83-0.91 across all doses, with 11/11 critical CD4-binding site contact residues preserved throughout. AlphaFold Multimer ipTM was consistent across all five immunogens (0.56-0.57), matching the eOD-GT8 baseline. An empirical safety limit of 28 residue substitutions per step was discovered.