A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies

HIV-specific CD8 + T-cells partially control viral replication and delay disease progression, but rarely provide lasting protection – largely due to immune escape. We show that engrafting mice with memory CD4+ T-cells from HIV + donors uniquely allows for the in vivo evaluation of autologous T-cell responses, while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically-relevant HIV-specific T-cell products resulted in substantial reductions in viremia, which were augmented by engineering with IL-15 superagonist-containing nanogels. Ultimately, in vivo activity was limited by the selection of diverse escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8 + T-cell response have a profound impact on the emergence and persistence of escape mutations. This ‘participant-derived xenograft’ model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.