 By down regulating cell surface expression of CD4 and Lck, Nef creates a narrow TCR response which likely optimizes HIV-1 viral production and generates a susceptible population of cells to further infect.Nef retargets kinase-active Lck away from the plasma membrane to early and recycling endosomes (RE) as well as the Trans-Golgi network (TGN).RE/TGN associated Lck sub-populations in Nef expressing cells are in the catalytically active conformation and thus signaling competent.