PMID- 28819312
OWN - NLM
STAT- MEDLINE
DCOM- 20190315
LR  - 20190315
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Aug 17
TI  - Shared peptide binding of HLA Class I and II alleles associate with cutaneous 
      nevirapine hypersensitivity and identify novel risk alleles.
PG  - 8653
LID - 10.1038/s41598-017-08876-0 [doi]
LID - 8653
AB  - Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins 
      involved in regulation of immune responses, and the way drugs interact with the 
      HLA peptide binding groove is important in the immunopathogenesis of T-cell 
      mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 
      antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) 
      associated with multiple class I and II HLA alleles. Here we utilize a novel 
      analytical approach to explore these multi-allelic associations by systematically 
      examining HLA molecules for similarities in peptide binding specificities and 
      binding pocket structure. We demonstrate that primary predisposition to cutaneous 
      NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C 
      alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent 
      association with 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 suggest drug-specific interactions within the antigen binding cleft can 
      be shared across HLA molecules with similar binding pockets. We thereby provide 
      an explanation for multiple HLA associations with cutaneous NVP HSR and advance 
      insight into its pathogenic mechanisms.
FAU - Pavlos, Rebecca
AU  - Pavlos R
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
FAU - McKinnon, Elizabeth J
AU  - McKinnon EJ
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
FAU - Ostrov, David A
AU  - Ostrov DA
AD  - University of Florida College of Medicine, Gainesville, FL, 32610, USA.
FAU - Peters, Bjoern
AU  - Peters B
AD  - La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
FAU - Buus, Soren
AU  - Buus S
AD  - Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, 
      DK-2200, Denmark.
FAU - Koelle, David
AU  - Koelle D
AD  - Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
AD  - Department of Global Health, University of Washington, Seattle, WA, 98195, USA.
AD  - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, 
      Seattle, WA, 98109-1024, USA.
AD  - Department of Laboratory Medicine, University of Washington, Seattle, WA, 98195, 
      USA.
AD  - Benaroya Research Institute, Seattle, WA, 98195, USA.
FAU - Chopra, Abha
AU  - Chopra A
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
FAU - Schutte, Ryan
AU  - Schutte R
AD  - University of Florida College of Medicine, Gainesville, FL, 32610, USA.
FAU - Rive, Craig
AU  - Rive C
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
FAU - Redwood, Alec
AU  - Redwood A
AUID- ORCID: 0000-0001-8601-8292
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
FAU - Restrepo, Susana
AU  - Restrepo S
AD  - University of Florida College of Medicine, Gainesville, FL, 32610, USA.
FAU - Bracey, Austin
AU  - Bracey A
AD  - University of Florida College of Medicine, Gainesville, FL, 32610, USA.
FAU - Kaever, Thomas
AU  - Kaever T
AD  - La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
FAU - Myers, Paisley
AU  - Myers P
AD  - Departments of Chemistry and Pathology, University of Virginia, Charlottesville, 
      VA, 222904, USA.
FAU - Speers, Ellen
AU  - Speers E
AD  - Departments of Chemistry and Pathology, University of Virginia, Charlottesville, 
      VA, 222904, USA.
FAU - Malaker, Stacy A
AU  - Malaker SA
AD  - Departments of Chemistry and Pathology, University of Virginia, Charlottesville, 
      VA, 222904, USA.
FAU - Shabanowitz, Jeffrey
AU  - Shabanowitz J
AD  - Departments of Chemistry and Pathology, University of Virginia, Charlottesville, 
      VA, 222904, USA.
FAU - Jing, Yuan
AU  - Jing Y
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 06877, USA.
FAU - Gaudieri, Silvana
AU  - Gaudieri S
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
AD  - School of Anatomy, Physiology and Human Biology, University of Western Australia, 
      Crawley, WA, 6009, Australia.
AD  - Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
FAU - Hunt, Donald F
AU  - Hunt DF
AD  - Departments of Chemistry and Pathology, University of Virginia, Charlottesville, 
      VA, 222904, USA.
FAU - Carrington, Mary
AU  - Carrington M
AUID- ORCID: 0000-0002-2692-2180
AD  - Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos 
      Biomedical Research Inc., Nashville, TN, 37232, USA.
AD  - Frederick National Laboratory for Cancer Research, Frederick, MD, 21702-1201, 
      USA.
AD  - Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA.
FAU - Haas, David W
AU  - Haas DW
AD  - Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
AD  - Meharry Medical College, Nashville, TN, 37208, USA.
FAU - Mallal, Simon
AU  - Mallal S
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia.
AD  - Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
FAU - Phillips, Elizabeth J
AU  - Phillips EJ
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, 
      WA, 6150, Australia. elizabeth.j.phillips@vanderbilt.edu.
AD  - Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. 
      elizabeth.j.phillips@vanderbilt.edu.
LA  - eng
GR  - UL1 TR000445/TR/NCATS NIH HHS/United States
GR  - R01 AI077505/AI/NIAID NIH HHS/United States
GR  - R13 AR071267/AR/NIAMS NIH HHS/United States
GR  - R01 AI103348/AI/NIAID NIH HHS/United States
GR  - P50 GM115305/GM/NIGMS NIH HHS/United States
GR  - P30 AI110527/AI/NIAID NIH HHS/United States
GR  - R01 AI033993/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20170817
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Peptides)
RN  - 99DK7FVK1H (Nevirapine)
SB  - IM
MH  - *Alleles
MH  - Anti-HIV Agents/administration & dosage/adverse effects
MH  - Case-Control Studies
MH  - Disease Susceptibility
MH  - Drug Hypersensitivity/*etiology/*metabolism
MH  - Histocompatibility Antigens Class I/chemistry/*genetics/*metabolism
MH  - Histocompatibility Antigens Class II/chemistry/*genetics/*metabolism
MH  - Humans
MH  - Nevirapine/administration & dosage/adverse effects
MH  - Odds Ratio
MH  - Peptides/chemistry/*metabolism
MH  - Protein Binding
MH  - Risk Assessment
MH  - T-Lymphocytes/immunology/metabolism
PMC - PMC5561238
COIS- S.M., E.J.P., and A.R. receive funding from the National Health and Medical 
      Research Council of Australia. S.M., E.J.P., D.O., B.P., D.K., S.B., D.H., and 
      D.F.H. hold grants from the National Institutes of Health/National Institute of 
      Allergy and Infectious Diseases. R.P., E.J.P., S.M., A.R., B.P. and D.O. receive 
      funding from the Australian Centre for HIV and Hepatitis Virology Research. E.M 
      was funded in part by NHMRC Australia. M.C. - This project has been funded in 
      whole or in part with federal funds from the Frederick National Laboratory for 
      Cancer Research, under Contract No. HHSN261200800001E. The content of this 
      publication does not necessarily reflect the views or policies of the Department 
      of Health and Human Services, nor does mention of trade names, commercial 
      products, or organizations imply endorsement by the U.S. Government. This 
      research was supported in part by the Intramural Research Program of the NIH, 
      Frederick National Lab, Center for Cancer Research. For the remaining authors no 
      conflicts of interest were declared. The funders had no role in study design, 
      data collection and analysis, decision to publish, or preparation of the 
      manuscript.
EDAT- 2017/08/19 06:00
MHDA- 2019/03/16 06:00
PMCR- 2017/08/17
CRDT- 2017/08/19 06:00
PHST- 2017/03/29 00:00 [received]
PHST- 2017/07/05 00:00 [accepted]
PHST- 2017/08/19 06:00 [entrez]
PHST- 2017/08/19 06:00 [pubmed]
PHST- 2019/03/16 06:00 [medline]
PHST- 2017/08/17 00:00 [pmc-release]
AID - 10.1038/s41598-017-08876-0 [pii]
AID - 8876 [pii]
AID - 10.1038/s41598-017-08876-0 [doi]
PST - epublish
SO  - Sci Rep. 2017 Aug 17;7(1):8653. doi: 10.1038/s41598-017-08876-0.