The Berlin patient who received allogeneic transplantation of bone marrow cells from an allogeneic donor who carried a mutation that rendered progeny cells resistant to HIV infection has shown that eradication of HIV is a realistic though difficult goal to reach. This strategy highlighted the positive impact of replacing the immune system of the infected host by cells that cannot be infected by HIV. Our group and others have used strategies less invasive than bone marrow transplantation to achieve the goal of replacing CD4 T cells that are susceptible to HIV infection by cells that are resistant to HIV infection. We have shown in single-arm studies that infusion of CCR5 modified autologous CD4 T cells leads to increased CD4 T cell numbers, down regulation of pro-inflammatory responses in cells of the innate and adaptive immune systems, and enhancement of HIV-specific T cell function; we showed in all subjects who received the modified cells a half log to 3 log10 decrease in total and integrated HIV DNA. This decline in HIV reservoir was associated with the expansion and long term persistence of a novel T cell subset (TSCM) that has features of stemness as these cells persisted for over 3 years and gave rise to progeny in all memory T cell subsets. Herein we propose a two arm double blinded controlled clinical trial designed to understand the role of ex vivo induced CCR5 modification (By Zn-finger nuclease) on the restoration of T cell homeostasis and function and the decay of HIV persistence in blood and lymphoid tissues . We will test the hypothesis that immune reconstitution with cells that are resistant to HIV infection results in a global improvement of immune homeostasis by downregulating the inflammation that drives immune senescence and triggers immune dysfunction and leads to the restoration of adaptive immunity that can control and eliminate residual HIV infected cells. One group of subjects (n=20) will be infused with CCR5 modified cells that are resistant to HIV infection while the other (n=10) will receive unmodified cells; both unmodified and modified cells will be expanded ex vivo using the same manufacturing procedures. In Aim 1 we will first test the hypothesis that subjects infused with CCR5-deleted cells will show dramatic decay of the replication competent HIV reservoir and then mechanistically confirm that this is related to CCR5 modification and not to ex vivo expansion alone by comparing this decay to changes in this reservoir seen in subjects infused with non-modified CD4 T cells. In Aim 2 we will test the hypothesis that this decay in HIV reservoir will be a consequence of expansion and persistence of an HIV resistant stem-cell-like subset of T cells (TSCM). In Aim 3 we will test the hypothesis that CD4 TSCM will restore immune homeostasis by reducing the pro-inflammatory milieu that prevails in cART-treated HIV-infected subjects which will result (Aim 4) in the restoration of an immune function capable of eliminating the ...