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

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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Gray LR,Cowley D,Welsh C,Lu HK,Brew BJ,Lewin SR,Wesselingh SL,Gorry PR,Churchill MJ

doi

10.1038/mp.2015.111

subject

Has Abstract

pub_date

2016-04-01 00:00:00

pages

574-84

issue

4

eissn

1359-4184

issn

1476-5578

pii

mp2015111

journal_volume

21

pub_type

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