Publications & Reports

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

Gray LR, Cowley D, Welsh C, Lu HK, Brew BJ, Lewin SR, Wesselingh SL, Gorry PR, Churchill MJ
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.


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.

This study was supported by grants from (i) the National Health and Medical Research Council of Australia (NHMRC) to MJC, PRG and SLW (APP1051093), (ii) and the National Institutes of Health (NIH) to MJC, PRG and SRL (R21 MH1022066) and (iii) the Delaney AIDS Research Enterprise (DARE) to MJC and SRL (U19 AI096109). PRG is supported by an Australian Research Council (ARC) Future Fellowship (FT2) and SRL is a NHMRC Practitioner Fellow. LRG was supported by an Australian NHMRC Early Career Fellowship. We gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.


  • Journal: Molecular Psychiatry
  • Published: 01/02/2016
  • Volume: 21
  • Issue: 4
  • Pagination: 574-584

Health Issue