CD4 CTLs were previously observed in HIV infection by Appay et al. and were defined as antigen experienced, terminally differentiated with CD8 CTLs-like phenotype i.e., CD27–CD28–CD45RO+CCR7-perf+gzmA+, and that their killing mechanism was granzyme and perforin dependent (10, 11). Here, CD28 is linked to HIV infectious disease.