Kidney Transplantation from Donors with HIV: Impact on Rejection and Long-term Outcomes

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. There are potential virologic and immunologic explanations for higher rejection in HIV D+/R+ vs D-/R+ KT. D+

kidneys harbor HIV and are more likely to harbor other co-infections such as CMV. These pathogens may trigger an inflammatory response, enhancing T-cell or antibody(Ab)-mediated pathways of rejection. Understanding the type of rejection and risk factors will inform interventions to improve outcomes, e.g. HIV D+

selection criteria, immunosuppression, or targeted monitoring and prophylaxis for co-infections. We propose Expanding HOPE, a multicenter trial comparing outcomes in 100 HIV D+/R+ KT and 100 D-/R+ KT at 15 transplant centers. We will combine this cohort with prior cohorts of HIV D+ and D- KT from our

HOPE in Action Consortium, established in 2015. HOPE in Action has accrued approximately 325 HIV+ KT recipients to date; this larger cohort provides sufficient statistical power to determine the impact of HIV D+ organ on rejection and it will also allow us to determine long-term patient and graft outcomes beyond 5-years.

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 use a multiplexed electrochemiluminescence detection assay to quantify >30 cytokine and chemokines to characterize inflammation, and phage display and immunoprecipitation sequencing to characterize Abs to >1300 viruses, >14,000 microbial toxins/virulence factors, and >27,000 human autoAbs.

Our HOPE in Action Multicenter Consortium has an established track record, successfully completing multicenter transplantation trials, including HIV D+/R+ KT. 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.