Barber and colleagues hypothesize that when patients with low CD4+ T cells acquire an opportunistic infection, subsequent paradoxical IRIS results from accumulated monocytes/macrophages harboring abundant organisms producing cytokines for cell signaling (e.g., IL-6), and then undergoing en masse activation upon an effective T cell response to produce excessive innate inflammatory cytokines. The gene discussed is CD4; the disease is Opportunistic infection.