Here, we have demonstrated that the binding of gp120 or HIV to immune cells (PBMCs, macrophages, THP-1, and CEM-GFP cell line reporter) triggers Panx-1 channel opening, sustained ATP secretion, and purinergic receptor activation, resulting in CXCR4/CCR5 clustering to enable proper HIV entry, RT activity, and replication – all essential points for HIV infection, silencing reactivation, and cure efforts. Here, ITIH4 is linked to HIV infectious disease.