Under the HIV Organ Policy Equity (HOPE) Act, early studies show that kidney transplantation (KT) from donors with HIV to recipients with HIV (HIV D+/R+) expands the donor pool, reduces wait-times, and yields excellent short-term patient and graft survival. However, significant rates of rejection were observed with a trend towards higher rates in D+ recipients compared to HIV-uninfected donor (D-) recipients. Understanding the impact of D+ on rejection, underlying mechanisms, and the impact on long-term outcomes is critical. We will combine this cohort with prior cohorts of HIV D+ and D- KT from our HOPE in Action Consortium, established in 2015. Within this trial, we will perform comprehensive mechanistic studies to examine both T-cell and Ab-mediated rejection pathways. We will quantify changes in donor-specific and viral-specific (HIV CMV) T cells using an activated induced marker (AIM) assay in D+ and D- recipients, with and without rejection, over time. We will perform TCRβ immunosequencing on sorted AIM+ cells vs unsorted T cells to track T cell receptor dynamics. With VDJ-specific PCR, we will quantify expanded clones, including donor or viral AIM+ cells, post-KT. We will also characterize inflammation and the humoral response to infections and human proteins (donor, self). We will leverage our existing infrastructure to oversee operations, data management, analysis, and safety monitoring. In summary, the proposed research will determine the impact of HIV+ donor kidneys on rejection, will quantify long term outcomes, and elucidate risks and mechanisms of rejection. This knowledge can improve and expand HIV D+/R+ KT, and can provide important insights about alloimmunity more broadly.