PMID- 26372480
OWN - NLM
STAT- MEDLINE
DCOM- 20160816
LR  - 20220129
IS  - 1473-5571 (Electronic)
IS  - 0269-9370 (Linking)
VI  - 29
IP  - 18
DP  - 2015 Nov 28
TI  - Towards depersonalized abacavir therapy: chemical modification eliminates 
      HLA-B*57 : 01-restricted CD8+ T-cell activation.
PG  - 2385-95
LID - 10.1097/QAD.0000000000000867 [doi]
AB  - OBJECTIVE: Exposure to abacavir is associated with T-cell-mediated 
      hypersensitivity reactions in individuals carrying human leukocyte antigen 
      (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous 
      HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting 
      cells. We have investigated whether chemical modification of abacavir can produce 
      a molecule with antiviral activity that does not bind to HLA-B57 : 01 and 
      activate T cells. DESIGN: An interdisciplinary laboratory study using samples 
      from human donors expressing HLA-B57 : 01. Researchers were blinded to the 
      analogue structures and modelling data. METHODS: Sixteen 6-amino substituted 
      abacavir analogues were synthesized. Computational docking studies were completed 
      to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive 
      CD8 clones were generated to study the association between HLA-B57 : 01 analogue 
      binding and T-cell activation. Antiviral activity and the direct inhibitory 
      effect of analogues on proliferation were assessed. RESULTS: Major 
      histocompatibility complex class I-restricted CD8 clones proliferated and 
      secreted IFNgamma following abacavir binding to surface and endogenous HLA-B57 : 01. 
      Several analogues retained antiviral activity and showed no overt inhibitory 
      effect on proliferation, but displayed highly divergent antigen-driven T-cell 
      responses. For example, abacavir and N-propyl abacavir were equally potent at 
      activating clones, whereas the closely related analogues N-isopropyl and N-methyl 
      isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to 
      HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding 
      and the T-cell response. CONCLUSION: These studies demonstrate that the unwanted 
      T-cell activity of abacavir can be eliminated whilst maintaining the favourable 
      antiviral profile. The in-silico model provides a tool to aid the design of safer 
      antiviral agents that may not require a personalized medicines approach to 
      therapy.
FAU - Naisbitt, Dean J
AU  - Naisbitt DJ
AD  - aMRC Centre for Drug Safety Science, Department of Molecular and Clinical 
      Pharmacology bDepartment of Chemistry, University of Liverpool, Liverpool, 
      England cLaboratory of Molecular Microbiology, National Institute of Allergy and 
      Infectious Diseases, National Institutes of Health, Maryland, USA dDrug 
      Metabolism and Pharmacokinetics, GlaxoSmithKline, Hertfordshire, England.
FAU - Yang, Emma L
AU  - Yang EL
FAU - Alhaidari, Mohammad
AU  - Alhaidari M
FAU - Berry, Neil G
AU  - Berry NG
FAU - Lawrenson, Alexandre S
AU  - Lawrenson AS
FAU - Farrell, John
AU  - Farrell J
FAU - Martin, Philip
AU  - Martin P
FAU - Strebel, Klaus
AU  - Strebel K
FAU - Owen, Andrew
AU  - Owen A
FAU - Pye, Matthew
AU  - Pye M
FAU - French, Neil S
AU  - French NS
FAU - Clarke, Stephen E
AU  - Clarke SE
FAU - O'Neill, Paul M
AU  - O'Neill PM
FAU - Park, B Kevin
AU  - Park BK
LA  - eng
GR  - G0700654/Medical Research Council/United Kingdom
GR  - MC_PC_13068/MRC_/Medical Research Council/United Kingdom
GR  - G0800247/MRC_/Medical Research Council/United Kingdom
GR  - MR/L006758/1/MRC_/Medical Research Council/United Kingdom
GR  - Biotechnology and Biological Sciences Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - AIDS
JT  - AIDS (London, England)
JID - 8710219
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Dideoxynucleosides)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B*57:01 antigen)
RN  - WR2TIP26VS (abacavir)
SB  - IM
MH  - Anti-HIV Agents/*adverse effects/chemistry/metabolism/pharmacology
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Dideoxynucleosides/*adverse effects/chemistry/metabolism/pharmacology
MH  - Drug Hypersensitivity/*prevention & control
MH  - HIV Infections/*drug therapy
MH  - HLA-B Antigens/*metabolism
MH  - Humans
MH  - Microbial Sensitivity Tests
MH  - Molecular Docking Simulation
MH  - Protein Binding
EDAT- 2015/09/16 06:00
MHDA- 2016/08/17 06:00
CRDT- 2015/09/16 06:00
PHST- 2015/09/16 06:00 [entrez]
PHST- 2015/09/16 06:00 [pubmed]
PHST- 2016/08/17 06:00 [medline]
AID - 10.1097/QAD.0000000000000867 [doi]
PST - ppublish
SO  - AIDS. 2015 Nov 28;29(18):2385-95. doi: 10.1097/QAD.0000000000000867.