This state of “Immune Exhaustion” is characterized by the upregulation of inhibitory co-receptors on CD4 and CD8 T cells such as PD-1 (135, 136), Tim-3 (137), CD160 (138), LAG-3 (139), and CTLA-4 (140) that correlate with markers of disease progression in chronic HIV infection (136, 137, 139–141). Here, CD4 is linked to HIV infectious disease.