Background: People who are living with HIV-1 have to maintain a lifetime of antiretrovirals, medication side effects and unsustainable costs to individual and society. Recently, “cure or functional cure” of HIV-1 infections was accomplished with the “Mississippi pediatric case”, proved that curing HIV-1 is possible. However, the cure treatment window, and the mechanisms of cure are unknown. In this study, curing HIV-1 with early treatment was tested in the humanized-BLT (hu-BLT) mouse model. Methodology: Six adult hu-BLT mice with good immune reconstitution were randomly divided into Early Treatment (Rx, n=3) and Control (Ctr, n=3) groups. Both groups were inoculated intraperitoneally (IP) with a mixture of two transmitted/founder HIV-1 viruses (2.5e3 TCID50 each). Six hours later, animals in the Rx group started daily treatment for two weeks with TDF, 5 mg/mouse, IP and 3TC, 4 mg/mouse, IP; Ctr animals received solvent IP. Three weeks after the antiretroviral drug therapy stopped, CD8+ T cells from both groups were depleted using two dose of anti-CD8 antibody (M-T807R1, 5mg/kg, IP) to test whether undetectable plasma viral load (PVL) was due to CD8+ T cells mediated viral control. Human CD8+ T cells in peripheral blood mononuclear cells (PBMCs) were quantified before and weekly after administration of anti-CD8 antibody using FLOW. Plasma viral RNA load (PVL), monitored weekly post inoculation (PI) using droplet digital PCR (ddPCR). HIV-1 viral DNA in PBMCs was monitored by ddPCR at 5 weeks post-CD8 depletion. Results: Ctr group PVL was positive from 7-10 days PI throughout the entire experiment (mean PVL 6.98e4 copies/ml week 1, increased to 2.5e6 copies/ ml at one month PI). In contrast, the Rx group had undetectable weekly PVL, including 3 weeks off therapy. To discriminate CD8+ T cells mediated cure in the Rx group, CD8+ T cells in both groups were depleted. CD8+ T cells comprised 27.6% +/-14.9% of total human CD3+ T cells in PBMCs before administration anti-CD8 antibody. After administration anti-CD8 antibody, 99.5 percent of CD8+ T cells were depleted over 5 weeks. CD8+ T cell depletion significantly increased PVL (mean +SD) in Ctr group (4.0e5 +/- 2.3e4 copies/ml before depletion to 2.7e6 + 2.7e5 at 3 weeks post depletion). In contrast, Rx group PVL remained undetectable and HIV-1 vDNA was undetectable in PBMCs. Conclusions: Early antiretroviral treatment can cure transmitted/founder HIV-1 infection in hu-BLT mouse model. Furthermore, CD8+ T cells depletion significantly elevated the PVL in Ctr animals, but did not modify the undetectable PVL in Rx group, suggesting early treatment achieved cure of HIV-1 infection. Studies are ongoing to further define the cure window and mechanisms involved.