Precision Medicine in Renal Transplantation: Structural Biology of HLA Defines Allelic Binding of Cardinal Pathogenic Viruses in Transplantation

K. R. Sherwood¹, A. Nguyen², J. Tran¹, O. Gunther³, A. Nellore², R. Thompson², J. Lan¹, L. Allan¹, P. A. Keown¹

¹Vancouver General Hospital, Vancouver, BC, Canada, ²Biomedical Engineering, Oregon Health & Science University, Portland, OR, ³Gunther Analytics, Vancouver, BC, Canada

Meeting: 2021 American Transplant Congress

Abstract number: LB 16

Keywords: Antigen presentation, Histocompatibility antigens, Immunogenicity

Topic: Clinical Science » Infectious Disease » All Infections (Excluding Kidney & Viral Hepatitis)

Session Information

Session Name: Late Breaking: Basic & ID

Session Type: Rapid Fire Oral Abstract

Date: Monday, June 7, 2021

Session Time: 6:00pm-7:00pm

Presentation Time: 6:35pm-6:40pm

Location: Virtual

*Purpose: The incidence, clearance and clinical expression of viremia post-Tx are heterogeneous, complicating prediction, prognosis and therapy. We postulated that variation viral presentation related to HLA type may inform understanding, and we used in silico methods to assess the MHC-peptide binding affinity for three important phylogenetically distinct viruses (SARS-CoV-2, CMV and BKV).

*Methods: Carrier frequencies for 11 HLA genes (HLA-A, B, C; DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1) were determined by NGS in 1150 renal transplant recipients. All FASTA-formatted viral protein sequence data from the NCBI RefSeq database were kmerized into 8-12 mers. Using netMHCpan, MHC-peptide binding affinities were predicted and affinity scores <500nM were included in the HLA allele rankings

*Results: A total of 206 Class I HLA alleles identified in 1150 patients exhibited population frequencies ranging from 0.09% to 30%. Within this repertoire, peptide binding varied dramatically identifying low- and high-affinity alleles for each of the three viral proteomes. Alleles with lowest binding propensity were specific to each virus (e.g. HLA-B*46:01 for SARS-CoV-2, HLA-B*51:05 for CMV and HLA-B*15:08 for BKV). In contrast, alleles with the highest binding propensity were remarkably uniform for all 3 viruses (e.g. HLA-A*02:11 top for all three virus proteomes). Sequence signatures for HLA isoforms in the same allele group defined high or low binding characteristics, the difference being conferred by as little as a single amino acid within the peptide binding region (e.g. HLA-B*15:08 vs B*15:03). Carrier rates for predicted SARS-CoV-2 susceptibility/resistance genes in the transplant population were observed to be similar to global population carrier rates (Fig 1).

*Conclusions: Evaluation of peptide binding provides a unique insight into viral recognition. If confirmed in our current proof-of-principle study comparing sequence and outcome in a large Canadian population, this data may offer a vital biomarker to define risk and treatment within conventional virological patient strata following transplant.

To cite this abstract in AMA style:

Sherwood KR, Nguyen A, Tran J, Gunther O, Nellore A, Thompson R, Lan J, Allan L, Keown PA. Precision Medicine in Renal Transplantation: Structural Biology of HLA Defines Allelic Binding of Cardinal Pathogenic Viruses in Transplantation [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/precision-medicine-in-renal-transplantation-structural-biology-of-hla-defines-allelic-binding-of-cardinal-pathogenic-viruses-in-transplantation/. Accessed November 21, 2024.

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