Faculty Bibliography

BACKGROUND:Kidney transplant (KT) candidates with HIV face higher mortality on the waitlist compared with candidates without HIV. Because the HIV Organ Policy Equity (HOPE) Act has expanded the donor pool to allow donors with HIV (D+), it is crucial to understand whether this has impacted transplant rates for this population. METHODS:Using a linkage between the HOPE in Action trial (NCT03500315) and Scientific Registry of Transplant Recipients, we identified 324 candidates listed for D+ kidneys (HOPE) compared with 46 025 candidates not listed for D+ kidneys (non-HOPE) at the same centers between April 26, 2018, and May 24, 2022. We characterized KT rate, KT type (D+, false-positive [FP; donor with false-positive HIV testing], D- [donor without HIV], living donor [LD]) and quantified the association between HOPE enrollment and KT rate using multivariable Cox regression with center-level clustering; HOPE was a time-varying exposure. RESULTS:HOPE candidates were more likely male individuals (79% versus 62%), Black (73% versus 35%), and publicly insured (71% versus 52%; P < 0.001). Within 4.5 y, 70% of HOPE candidates received a KT (41% D+, 34% D-, 20% FP, 4% LD) versus 43% of non-HOPE candidates (74% D-, 26% LD). Conversely, 22% of HOPE candidates versus 39% of non-HOPE candidates died or were removed from the waitlist. Median KT wait time was 10.3 mo for HOPE versus 60.8 mo for non-HOPE candidates (P < 0.001). After adjustment, HOPE candidates had a 3.30-fold higher KT rate (adjusted hazard ratio = 3.30, 95% confidence interval, 2.14-5.10; P < 0.001). CONCLUSIONS:Listing for D+ kidneys within HOPE trials was associated with a higher KT rate and shorter wait time, supporting the expansion of this practice for candidates with HIV.

The latent viral reservoir(LVR) remains a major barrier to HIV-1 curative strategies. It is unknown whether receiving a liver transplant from a donor with HIV might lead to an increase in the LVR since the liver is a large lymphoid organ. We found no differences in intact provirus, defective provirus, or the ratio of intact to defective provirus between recipients with ART-supporesed HIV who received a liver from a donor with(n = 19) or without HIV(n = 10). All measures remained stable from baseline by one-year post transplant. These data demonstrate that the LVR is stable after liver transplantation in people living with HIV.

BACKGROUND:Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach. METHODS:We did a complete phenotyping of two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling and cell deconvolution. Xenografts before implantation, wild-type pig kidney autografts, as well as wild-type, non-transplanted pig kidneys with and without ischaemia-reperfusion were used as controls. FINDINGS:cells. Both xenografts showed increased expression of genes biologically related to a humoral response, including monocyte and macrophage activation, natural killer cell burden, endothelial activation, complement activation, and T-cell development. Whole-transcriptome digital spatial profiling showed that antibody-mediated injury was mainly located in the glomeruli of the xenografts, with significant enrichment of transcripts associated with monocytes, macrophages, neutrophils, and natural killer cells. This phenotype was not observed in control pig kidney autografts or in ischaemia-reperfusion models. INTERPRETATION:Despite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results. FUNDING:OrganX and MSD Avenir.

BACKGROUND:Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS:We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS:Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS:SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

This guidance was developed to summarize current approaches to the potential transmission of swine-derived organisms to xenograft recipients, health care providers, or the public in clinical xenotransplantation. Limited specific data are available on the zoonotic potential of pig pathogens. It is anticipated that the risk of zoonotic infection in xenograft recipients will be determined by organisms present in source animals and relate to the nature and intensity of the immunosuppression used to maintain xenograft function. Based on experience in allotransplantation and with preclinical models, viral infections are of greatest concern, including porcine cytomegalovirus, porcine lymphotropic herpesvirus, and porcine endogenous retroviruses. Sensitive and specific microbiological assays are required for routine microbiological surveillance of source animals and xenograft recipients. Archiving of blood samples from recipients, contacts, and hospital staff may provide a basis for microbiological investigations if infectious syndromes develop. Carefully implemented infection control practices are required to prevent zoonotic pathogen exposures by clinical care providers. Informed consent practices for recipients and their close contacts must convey the lack of specific data for infectious risk assessment. Available data suggest that infectious risks of xenotransplantation are manageable and that clinical trials can advance with carefully developed protocols for pretransplant assessment, syndrome evaluation, and microbiological monitoring.

New mutations conferring resistance to SARS-CoV-2 therapeutics have important clinical implications. We describe the first cases of an independently acquired V792I RNA-dependent RNA polymerase mutation developing in renal transplant recipients after remdesivir exposure. Our work underscores the need for augmented efforts to identify concerning mutations and address their clinical implications.

The HIV latent viral reservoir (LVR) remains a major challenge in the effort to find a cure for HIV. There is interest in lymphocyte-depleting agents, used in solid organ and bone marrow transplantation to reduce the LVR. This study evaluated the LVR and T cell receptor repertoire in HIV-infected kidney transplant recipients using intact proviral DNA assay and T cell receptor sequencing in patients receiving lymphocyte-depleting or lymphocyte-nondepleting immunosuppression induction therapy. CD4+ T cells and intact and defective provirus frequencies decreased following lymphocyte-depleting induction therapy but rebounded to near baseline levels within 1 year after induction. In contrast, these biomarkers were relatively stable over time in the lymphocyte-nondepleting group. The lymphocyte-depleting group had early TCRβ repertoire turnover and newly detected and expanded clones compared with the lymphocyte-nondepleting group. No differences were observed in TCRβ clonality and repertoire richness between groups. These findings suggest that, even with significant decreases in the overall size of the circulating LVR, the reservoir can be reconstituted in a relatively short period of time. These results, while from a relatively unique population, suggest that curative strategies aimed at depleting the HIV LVR will need to achieve specific and durable levels of HIV-infected T cell depletion.

BACKGROUND:Organ transplantation from donors with HIV to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV+ donors is critical for safety. METHODS:We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) testing within the HOPE in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262; NCT03500315; NCT03734393). We compared clinical characteristics in HIV+ versus FP donors. We measured CD4+ T cells, HIV viral load (VL), drug resistance mutations (DRMs), co-receptor tropism, and serum antiretroviral therapy (ART) detection using mass spectrometry in HIV+ donors. RESULTS:Between 03/2016-03/2020, 92 donors (58 HIV+, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidney, 46 liver). Each year the number of donors increased. Prevalence of hepatitis B (16% vs. 0%), syphilis (16% vs. 0%), and cytomegalovirus (91% vs. 58%) was higher in HIV+ versus FP donors; hepatitis C viremia was similar (2% vs. 6%). Most HIV+ donors (71%) had known HIV diagnosis, of whom 90% were prescribed ART and 68% had VL<400 copies/mL. Median CD4 count was 194 cells/uL (IQR=77-331); median CD4% was 27.0 (IQR=16.8-36.1). Major HIV DRMs were detected in 42%, including non-nucleoside reverse transcriptase inhibitors (33%), integrase strand transfer inhibitor (INSTI, 4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION/CONCLUSIONS:Utilization of HIV+ donor organs is increasing. HIV DRMs are common, yet resistance that would compromise INSTI-based regimens is rare, which is reassuring regarding safety.