System biology reveals a mechanism associated with protection by the co-immunization of DNA and protein in the same anatomical site

System immunology was used to identify the mechanisms linked to the immunogenicity and protective efficacy of an HIV vaccine comprised of Env and Gag DNA and Env proteins by co-administration of the vaccine components in the same muscles or by separate administration of DNA and protein in contralateral sites in female rhesus macaques. Interestingly, only macaques in the co-administration vaccine group were protected against SHIV CH505 acquisition after repeated low-dose intravaginal challenge and showed 67% risk reduction per exposure. Macaques in the co-administration group developed higher migratory monocytes (CXCR4+ monocytes with increased LYN expression) from blood to lymph nodes. The heightened frequency of those migratory monocytes was associated with heightened ADCC pre-challenge and with decreased risk of acquisition. These data suggest that monocytes migration is key to the simultaneous recognition, processing and presentation of DNA+Env protein in the same draining lymph nodes to confer protective immunity. Blood bulk RNA-seq (paired-end strand-specific) for 505 samples and 24 controls. Samples were collected from 20 rhesus macaques that receive DNA and protein in both legs and 19 rhesus animals that received DNA and protein in different legs