dc.contributor.author |
Fonteh, Pascaline Nanga
|
|
dc.contributor.author |
Meyer, Debra
|
|
dc.date.accessioned |
2015-02-17T09:38:32Z |
|
dc.date.available |
2015-02-17T09:38:32Z |
|
dc.date.issued |
2014-12 |
|
dc.description.abstract |
BACKGROUND : A number of cytostatic agents have been investigated for the ability to reactivate latent viral
reservoirs, which is a major prerequisite for the eradication of HIV-1 infection. Two cytostatic bis(thiosemicarbazonate)
gold(III) complexes (designated 1 and 2) were tested for this potential in the U1 latency model of HIV-1 infection.
METHODS : Cell viability in the presence or absence of 1 and 2 was determined using a tetrazolium dye and evidence of
reactivation was assessed by p24 antigen capture following exposure to a latency stimulant, phorbol myristate acetate
(PMA) and or test compounds. The latency reactivation mechanism was explored by determining the effect of the
complexes on protein kinase C (PKC), histone deacetylases (HDAC) and proinflammatory cytokine production.
RESULTS : The CC50 of the complexes in U1 cells were 0.53 ± 0.12 μM for 1 and 1.0 ± 0.4 μM for 2. In the absence of PMA
and at non toxic concentrations of 0.2 and 0.5 μM, 1 and 2 significantly (p ≤ 0.02) reactivated virus in U1 cells by 2.7
and 2.3 fold respectively. In comparison, a 2.6 fold increase (p = 0.03) in viral reactivation was observed for hydroxyurea
(HU), which was used as a cytostatic and latent HIV reactivation control. Viral reactivation was absent for the complexes
during co-stimulation with PMA indicating the lack of an additive effect between the chemicals as well as an absence
of inhibition of PMA induced HIV reactivation but for HU inhibition of the stimulant’s activity was observed (p = 0.01).
Complex 1 and 2 activated PKC activity by up to 32% (p < 0.05) but no significant inhibition of HDAC was observed.
Increases in TNF-α levels suggested that the reactivation of virus by the complexes may have been due to contributions
from the latter and the activation of PKC.
CONCLUSION : The ethyl group structural difference between 1 and 2 seems to influence bioactivity with lower active
concentrations of 1, suggesting that further structural modifications should improve specificity. The cytostatic effect of 1
and 2 and now HIV reactivation from a U1 latency model is consistent with that of the cytostatic agent, HU. These
findings suggest that the complexes have a potential dual (cytostatic and reactivation) role in viral “activation/elimination”. |
en_ZA |
dc.description.librarian |
hb2015 |
en_ZA |
dc.description.sponsorship |
AuTEK Biomed (Mintek and Harmony Gold),Technology Innovation Agency (TIA) and the University of Pretoria. |
en_ZA |
dc.description.uri |
http://www.biomedcentral.com/bmcinfectdis/ |
en_ZA |
dc.identifier.citation |
Fonteh, P & Meyer, D 2014, 'In vitro reactivation of latent HIV-1 by cytostatic bis (thiosemicarbazonate) gold(III) complexes', BMC Infectious Diseases, vol. 14, art. 680, pp. 1-9. |
en_ZA |
dc.identifier.issn |
1471-2334 (print) |
|
dc.identifier.other |
10.1186/s12879-014-0680-3 |
|
dc.identifier.uri |
http://hdl.handle.net/2263/43691 |
|
dc.language.iso |
en |
en_ZA |
dc.publisher |
BioMed Central |
en_ZA |
dc.rights |
© 2014 Fonteh and Meyer; licensee 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 credited. 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. |
en_ZA |
dc.subject |
HIV eradication |
en_ZA |
dc.subject |
Latent virus reactivation |
en_ZA |
dc.subject |
Bis(thiosemicarbazonate) gold(III) complexes |
en_ZA |
dc.subject |
TNF-α |
en_ZA |
dc.subject |
Human immunodeficiency virus (HIV) |
en_ZA |
dc.subject |
Protein kinase C (PKC) |
en_ZA |
dc.title |
In vitro reactivation of latent HIV-1 by cytostatic bis (thiosemicarbazonate) gold(III) complexes |
en_ZA |
dc.type |
Article |
en_ZA |