In summary, we hypothesize that immune activation in foreskin tissues adjacent to the sub-preputial space facilitates HIV infection through a combination of epithelial barrier disruption, enhanced dendritic cell maturation, and the recruitment/activation of neutrophils and susceptible CD4 T-cell subsets such as Th17 cells, and that the genital microbiome may be an important driver of this immune activation. The gene discussed is CD4; the disease is HIV infectious disease.