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CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2016 Apr; Vol. 21 (4), pp. 574-84. Date of Electronic Publication: 2015 Aug 25. - Publication Year :
- 2016
-
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.
- Subjects :
- Adult
Brain metabolism
CD4-Positive T-Lymphocytes
Central Nervous System metabolism
Cohort Studies
Depsipeptides pharmacology
HIV Infections drug therapy
HIV-1 genetics
Humans
Hydroxamic Acids pharmacology
Indoles pharmacology
Jurkat Cells
Male
Middle Aged
Panobinostat
Polymorphism, Genetic
Terminal Repeat Sequences
Transcriptional Activation
Virus Latency drug effects
Brain virology
HIV Infections virology
HIV-1 physiology
Histone Deacetylase Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 21
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 26303660
- Full Text :
- https://doi.org/10.1038/mp.2015.111