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Updated: Apr 5, 2026
High Throughput In Vitro Assessment of Latency Reversing Agents on HIV Transcription and Splicing
Published on: January 22, 2019
CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with
L R Gray1,2, D Cowley3, C Welsh1
1Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.
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.
Insights
Latency-reversing agents may be less effective against central nervous system HIV-1 strains. These strains have unique genetic variations in their long terminal repeat regions, reducing their response to latency-reversing therapies.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Latency-reversing agents (LRAs) are being studied to eliminate latent HIV.
- Histone deacetylase inhibitors (HDACi) are a class of LRAs.
- Effectiveness of LRAs against central nervous system (CNS) HIV strains is unknown.
Purpose of the Study:
- To investigate the effectiveness of LRAs against CNS-derived HIV-1 strains.
- To understand the transcriptional regulation of CNS-derived HIV-1.
- To inform HIV eradication strategies.
Main Methods:
- Analysis of polymorphisms in long terminal repeat (LTR) regions of CNS-derived HIV-1 strains.
- Assessment of Sp transcription factor binding to CNS-derived LTRs.
- Evaluation of CNS-derived and lymphoid-derived HIV-1 responsiveness to HDACi (panobinostat, romidepsin).
Main Results:
- CNS-derived HIV-1 strains exhibit polymorphisms in Sp transcription factor motifs within the LTR.
- These polymorphisms reduce Sp1 binding affinity and transcriptional activity of CNS-derived viruses.
- CNS-derived HIV-1 strains are less responsive to HDACi activation compared to lymphoid-derived strains.
Conclusions:
- HIV-1 strains in the CNS possess distinct transcriptional regulatory mechanisms.
- These unique mechanisms impact latency regulation and LRA effectiveness.
- Understanding CNS-specific HIV regulation is crucial for developing effective HIV eradication strategies.
