Here, we comprehensively show for the first time that HIV-1 exploits cell-to-cell spread to efficiently infect resting memory CD4+ T cells, and we have used this to uncover a hitherto unknown consequence of HIV-1 infection for T cell reprogramming driven by the accessory protein Vpr, inducing cells to gain characteristics of tissue-resident memory T cells. The gene discussed is CD4; the disease is HIV-1 infection.