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Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT. [Display omitted] • Allogeneic immunity clears SIV reservoirs after allogeneic stem cell transplant • Post-transplant SIV reservoir clearance occurs stepwise, first in blood, then tissues • CCR5+ allogeneic HSCT can functionally cure macaques of SIV • SIV spreads to engrafting CCR5+ donor cells despite fully suppressive therapy The only cases of HIV cure were achieved through CCR5-deficient allogeneic stem cell transplantation, but the precise mechanisms mediating cure remain unknown. Wu et al. use a nonhuman primate model to demonstrate that allogeneic immunity is the major driver of virus clearance following alloHSCT but can be thwarted by viral spread to engrafting CCR5+ donor cells despite suppressive anti-retroviral therapy. [ABSTRACT FROM AUTHOR]