Volume 4 Supplement 3

6th Drug Hypersensitivity Meeting (DHM 6)

Open Access

Chemical modification of the 6'-amino cyclopropyl of abacavir eliminates HLA-B*57:01-restricted CD8+ T-cell activation without loss of antiviral activity

  • Mohammad Alhaidari1,
  • Emma Yang1,
  • Neil Berry1,
  • Andrew Owen1,
  • Steve Clarke2,
  • Paul O'Neill1,
  • Dean Naisbitt1 and
  • Kevin Park1
Clinical and Translational Allergy20144(Suppl 3):P40

https://doi.org/10.1186/2045-7022-4-S3-P40

Published: 18 July 2014

Background

Abacavir, a nucleoside reverse transcriptase inhibitor, is used within drug combination therapy to treat the HIV-1 virus. It is a guanosine-analogue pro-drug, and once metabolised to carbovir, it acts as a DNA chain terminator. Exposure to abacavir is associated with a high frequency of CD8+ T-cell-mediated hypersensitivity reactions in individuals carrying the HLA risk allele B*57:01. To activate T-cells, abacavir interacts directly with endogenous HLA-B*57:01, altering the repertoire of peptides displayed on the cell surface. Docking studies show that the amino cyclopropyl group at the 6-position of abacavir assists in the arrangement and interaction of peptides with the MHC binding pocket. We hypothesized that chemical modification of abacavir at this position would provide a new series of analogues with potent antiviral activity that do not activate abacavir-specific CD8+ T-cells.

Methods

Fifteen analogues were synthesized and their anti-viral activity measured. T cell responses to these analogues was then measured using CD8+ clones generated from HLA-B*57:01+ donors.

Results

Several analogues, including the key closely related compounds, retained antiviral activity, but displayed highly divergent T-cell responses. Three HLA-B*57:01 positive blood donors were selected to generate abacavir-responsive T-cell clones. IFN- release was visualized using ELISpot to measure abacavir-specific T-cell responses and to determine which analogues activated the T-cells. All of the abacavir-responsive clones secreted IFN-, in a drug-concentration-dependent fashion (EC50 [50% of maximal IFN- spot forming units] less than 20M for all clones). A minimum of 5 clones were used to compare abacavir specific responses against the analogues. Abacavir and N-propyl abacavir were equally potent at activating clones. In contrast, two very closely related abacavir analogues were devoid of T-cell activity.

Conclusion

Our findings show that it is possible to block the T-cell activity of abacavir while maintaining anti-viral activity by simple chemical modification.

Authors’ Affiliations

(1)
University of Liverpool, MRC Centre for Drug Safety Science
(2)
GlaxoSmithKline, Drug Metabolism & Pharmacokinetics

Copyright

© Alhaidari et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement