HIV latency is a major obstacle to curing infection. Current strategies to eradicate HIV aim at increasing transcription of the latent provirus. In the present study we observed that latently infected CD4+ T cells from HIV-infected individuals failed to produce viral particles upon ex vivo exposure to SAHA (vorinostat), despite effective inhibition of histone deacetylases. To identify steps that were not susceptible to the action of SAHA or other latency reverting agents, we used a primary CD4+ T cell model, joint host and viral RNA sequencing, and a viral-encoded reporter. This model served to investigate the characteristics of latently infected cells, the dynamics of HIV latency, and the process of reactivation induced by various stimuli. During latency, we observed persistence of viral transcripts but only limited viral translation. Similarly, the reactivating agents SAHA and disulfiram successfully increased viral transcription, but failed to effectively enhance viral translation, mirroring the ex vivo data. This study highlights the importance of post-transcriptional blocks as one mechanism leading to HIV latency that needs to be relieved in order to purge the viral reservoir.
HIV-infected individuals must receive lifelong antiviral therapy because treatment discontinuation generally results in rapid viral rebound. The field has identified a state of latency at the level of transcription of the integrated provirus as the major mechanism of persistence. A number of drugs are now tested that aim at inducing viral transcription as a step to purge the reservoir. The assessment of viral production in cells from HIV-infected individuals with optimal viral suppression revealed the failure of SAHA/vorinostat to efficiently generate viral particle production. To further investigate and characterize the process of latency at the transcriptome level, and the response to SAHA as well as various reactivating agents, we use a model of primary CD4+ lymphocytes. The main observation from this study is that viral transcripts persist during latency, and that the accumulation of viral transcripts does not result in efficient viral protein expression upon reactivation with agents such as SAHA. Our data suggest that post-transcriptional blocks also contribute to latency, and that additional strategies need to be explored to efficiently purge the viral reservoir.