S1, Elizabeth J. McKinnon1, David A. Emixustat MedChemExpress Ostrov2, Bjoern Peters3, Soren Buus4, David Koelle5,6,7,8,9, Abha Chopra1, Ryan Schutte2, Craig Rive1, Alec Redwood 1, Susana Restrepo2, Austin Bracey2, Thomas Kaever3, Paisley Myers10, Ellen Speers10, Stacy A. Malaker10, Jeffrey Shabanowitz10, Yuan Jing11, Silvana Gaudieri1,12,13, Donald F. Hunt10, Mary Carrington 14,15,16, David W. Haas13,17, Simon Mallal1,13 Elizabeth J. Phillips1,Genes in the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, plus the way drugs interact with the HLA peptide binding groove is vital in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is definitely an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with numerous class I and II HLA alleles. Here we utilize a novel analytical strategy to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that key predisposition to cutaneous NVP HSR, noticed across ancestral groups, could be attributed to a cluster of HLA-C alleles sharing a typical binding groove F pocket with HLA-C04:01. An independent association having a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results recommend drug-specific interactions inside the antigen binding cleft could be shared across HLA molecules with comparable binding pockets. We thereby provide an explanation for various HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms. Adverse drug reactions are related with considerable worldwide morbidity and mortality and pose a substantial challenge in drug development and implementation. A subset of these reactions are T-cell mediated and associateInstitute for Immunology and Infectious Ailments, Murdoch University, Murdoch, WA, 6150, Australia. 2University of Florida College of Medicine, Gainesville, FL, 32610, USA. 3La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA. 4Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, DK-2200, Denmark. 5Department of Medicine, University of Washington, Seattle, WA, 98195, USA. 6Department of Global Health, University of Washington, Seattle, WA, 98195, USA. 7Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Analysis Center, Seattle, WA, 98109-1024, USA. 8Department of Laboratory Medicine, University of Washington, Seattle, WA, 98195, USA. 9Benaroya Study Institute, Seattle, WA, 98195, USA. 10 Departments of Chemistry and Pathology, University of Virginia, Charlottesville, VA, 222904, USA. 11Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 06877, USA. 12School of Anatomy, Physiology and Human Biology, University of Western 1-Methylhistamine supplier Australia, Crawley, WA, 6009, Australia. 13Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. 14Cancer and Inflammation Plan, Laboratory of Experimental Immunology, Leidos Biomedical Analysis Inc., Nashville, TN, 37232, USA. 15Frederick National Laboratory for Cancer Investigation, Frederick, MD, 21702-1201, USA. 16Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA. 17Meharry Healthcare College, Nashville, TN, 37208, USA. Rebecca Pavlos a.