CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies

Gray, L, Cowley, D, Welsh, C, Lu, H, Brew, B, Lewin, S, Wesselingh, S, Gorry, P and Churchill, M 2016, 'CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies', Molecular Psychiatry, vol. 21, no. 4, pp. 574-584.


Document type: Journal Article
Collection: Journal Articles

Title CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies
Author(s) Gray, L
Cowley, D
Welsh, C
Lu, H
Brew, B
Lewin, S
Wesselingh, S
Gorry, P
Churchill, M
Year 2016
Journal name Molecular Psychiatry
Volume number 21
Issue number 4
Start page 574
End page 584
Total pages 11
Publisher Nature Publishing Group
Abstract Latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACi), are being investigated as a strategy to eliminate latency in HIV-infected patients on suppressive antiretroviral therapy. The effectiveness of LRAs in activating latent infection in HIV strains derived from the central nervous system (CNS) is unknown. Here we show that CNS-derived HIV-1 strains possess polymorphisms within and surrounding the Sp transcription factor motifs in the long terminal repeat (LTR). These polymorphisms result in decreased ability of the transcription factor specificity protein 1 to bind CNS-derived LTRs, reducing the transcriptional activity of CNS-derived viruses. These mutations result in CNS-derived viruses being less responsive to activation by the HDACi panobinostat and romidepsin compared with lymphoid-derived viruses from the same subjects. Our findings suggest that HIV-1 strains residing in the CNS have unique transcriptional regulatory mechanisms, which impact the regulation of latency, the consideration of which is essential for the development of HIV-1 eradication strategies.
Subject Biological Sciences not elsewhere classified
DOI - identifier 10.1038/mp.2015.111
Copyright notice © 2016 Macmillan Publishers Limited.This work is licensed under a Creative Commons AttributionNonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/
ISSN 1359-4184
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